145 replies to this topic

[fishinghat]

Prescription Meds (cont)

Limited effectiveness/Long-term use and Addiction
http://www.ncbi.nlm....pubmed/16933543
The Canadian Psychiatric Association (CPA) recommends benzodiazepines alprazolam, bromazepam, lorazepam, and diazepam only as a second-line choice, if the treatment with two different antidepressants was unsuccessful. Although they are second-line agents, benzodiazepines can be used for a limited time to relieve severe anxiety and agitation. CPA guidelines note that after 4–6 weeks the effect of benzodiazepines may decrease to the level of placebo, and that benzodiazepines are less effective than antidepressants in alleviating ruminative worry, the core symptom of GAD. However, in some cases, a prolonged treatment with benzodiazepines as the add-on to an antidepressant may be justified.

https://www.ncbi.nlm...pubmed/16639148
Tolerance to anti-anxiety effects develops more slowly with little evidence of continued effectiveness beyond four to six months of continued use.

Curran, H. V.; Collins, R.; Fletcher, S.; Kee, S. C. Y.; Woods, B.; Iliffe, S. (2003-10-01). "Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life". Psychological Medicine 33 (7): 1223–1237. doi:10.1017/s0033291703008213. ISSN 0033-2917. PMID 14580077.
"Holbrook AM. %282004%29. Treating insomnia. - PubMed - NCBI". www.ncbi.nlm.nih.gov. PMID 25282004. Retrieved 2015-12-10.

Poyares, Dalva; Guilleminault, Christian; Ohayon, Maurice M.; Tufik, Sergio (2004-06-01). "Chronic benzodiazepine usage and withdrawal in insomnia patients". Journal of Psychiatric Research 38 (3): 327–334. doi:10.1016/j.jpsychires.2003.10.003. ISSN 0022-3956. PMID 15003439.

Friedman MJ (1998). "Pharmacotherapy for posttraumatic stress disorder: a status report". Clinical Neurosciences Supplement 52: S115–S121.

Heather N, Bowie A, Ashton H, McAvoy B, Spencer I, Brodie J, Giddings D (2004). "Randomised controlled trial of two brief interventions against long-term benzodiazepine use: outcome of intervention". Addiction Research and Theory 12 (2): 141–154. doi:10.1080/1606635310001634528.

Bandelow, Borwin; Zohar, Joseph; Hollander, Eric; Kasper, Siegfried; Möller, Hans-Jürgen; Zohar, Joseph; Hollander, Eric; Kasper, Siegfried (2008-01-01). "World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders http://www.ncbi.nlm....ubmed/18949648"The World Journal of Biological Psychiatry 9 (4): 248–312. doi:10.1080/15622970802465807. ISSN 1562-2975. PMID 18949648.

Ashton, Heather (2005-05-01). "The diagnosis and management of benzodiazepine dependence". Current Opinion in Psychiatry 18 (3): 249–255. doi:10.1097/01.yco.0000165594.60434.84. ISSN 0951-7367. PMID 16639148.

Morin, Charles M.; Bélanger, Lynda; Bastien, Célyne; Vallières, Annie (2005-01-01). "Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse". Behaviour Research and Therapy 43 (1): 1–14. doi:10.1016/j.brat.2003.12.002. ISSN 0005-7967. PMID 15531349.

Michelini S, Cassano GB, Frare F, et al. (2016). "Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders.". Pharmacopsychiatry 29: 127–134
http://www.ncbi.nlm....pubmed/24434093
Several studies (listed above) have confirmed that long-term benzodiazepines are not significantly different from placebo for sleep or anxiety. This may explain why patients commonly increase doses over time and many eventually take more than one type of benzodiazepine after the first loses effectiveness.

https://www.ncbi.nlm...pubmed/15078112
Discontinuation of benzodiazepines or abrupt reduction of the dose, even after a relatively short course of treatment (three to four weeks), may result in two groups of symptoms—rebound and withdrawal. Rebound symptoms are the return of the symptoms for which the patient was treated but worse than before. Withdrawal symptoms are the new symptoms that occur when the benzodiazepine is stopped. They are the main sign of physical dependence.

https://www.ncbi.nlm...pubmed/26164054
While benzodizapines may have short-term benefits for anxiety, sleep and agitation in some patients, long-term (i.e., greater than 2–4 weeks) use can result in a worsening of the very symptoms the medications are meant to treat.

https://www.ncbi.nlm...pubmed/26545257
The relative proportion of long-term BZD users in adult BZD users ranged from 6% to 76% (mean 24%) The estimates were higher in studies only on the elderly (47%). Long-term use involved typically steady treatment with low BZD doses. However, in elderly patients long-term BZD use and exceeding recommended doses was relatively common. Several characteristics associated with long-term use were found.

https://www.ncbi.nlm.../pubmed/2222129
Patients who were able to remain free of benzodiazepines for at least 5 weeks obtained lower levels of anxiety than before benzodiazepine discontinuation.
Effects of long-term use.
Alzheimer's Disease
https://www.ncbi.nlm...pubmed/26011780
During the 4-year follow-up, we found that 45% of individuals with Alzheimer's Disease (AD) and 38% of individuals without AD used BZDRs. The prevalence of long-term (≥ 180 days) BZDR use was more common among individuals with AD (30%) than individuals without AD (26%). The high prevalence of long-term BZDR use among individuals with AD is especially a cause for concern because long-term use may further impair cognition and may be associated with serious adverse events.

https://www.ncbi.nlm...pubmed/25208536
No association for Alzheimer's disease was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density 1.32 for 91-180 prescribed daily doses and 1.84 for >180 prescribed daily doses). Benzodiazepine use is associated with an increased risk of Alzheimer's disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.

https://www.ncbi.nlm...pubmed/25491057
Taking benzodiazepine is associated with an increased risk of Alzheimer disease

Cancer Risk
https://www.ncbi.nlm...pubmed/25674736
Clonazepam was associated with a higher risk for cancers. Moreover, specific cancer risk among BZDs use was observed significantly increased 98% for brain, 25% for colorectal, and 10% for lung, as compared with non-BZDs use. Diazepam, chlordiazepoxide, medazepam, nitrazepam, and oxazepam are safe among BZDs use for cancer risk.

https://www.ncbi.nlm...pubmed/24314718
In this population-based study, we found a significant increase in the risk of benign brain tumor development in a cohort of long-term (>2 months) BZD users.

https://www.ncbi.nlm...pubmed/23043261
BZD use was not associated with an overall increase in cancer risk.

Dementia
https://www.ncbi.nlm...pubmed/25691075
Out of the ten studies retrieved, nine reported an increased risk of dementia in benzodiazepine users. The risk increased with cumulative dose and treatment duration and when long-acting molecules were used. Even if the causal nature of this association remains unproved, the reviewed material provides arguments for evoking a causal link. Further research would be necessary to elucidate the mechanism of this effect, if any, to evaluate the risk of exposure in younger population and the influence of risk factors such as depression. In any case, the body of evidence seems sufficient for avoiding prescriptions or renewals that are not fully justified and indiscriminate long-term use.

https://www.ncbi.nlm...pubmed/26016483
The risk of dementia increased by 22% for every additional 20 defined daily dose per year. Long-term benzodiazepine users have an increased risk of dementia compared with never users.

https://www.ncbi.nlm...les/PMC4737849/
The risk of dementia is slightly higher in people with minimal exposure to benzodiazepines but not with the highest level of exposure. These results do not support a causal association between benzodiazepine use and dementia.

https://www.ncbi.nlm...les/PMC3460255/
In this prospective population based study, new use of benzodiazepines was associated with increased risk of dementia. The result was robust in pooled analyses across cohorts of new users of benzodiazepines throughout the study and in a complementary case-control study.

Memory/Cognative Function
https://www.ncbi.nlm...pubmed/21494764
In the course of the 10 year-follow-up, 3.9% of subjects were defined as occasional users of benzodiazepine and 7.5% as long-term users. The analysis revealed a significant alteration of long-term memory in women whereas there was no significant association in men.

https://www.ncbi.nlm...pubmed/22705064
Chronic use of benzodiazepine was significantly associated with a lower latent cognitive level, but no association was found between chronic use and an acceleration of cognitive decline, neither on the latent cognitive process, nor on specific neuropsychological tests. Our results suggest that chronic benzodiazepine use is associated with poorer cognitive performance but not with accelerated cognitive decline with age.

https://www.ncbi.nlm.../pubmed/7639085
This study confirmed earlier observations of neuropsychological deficits in long-term benzodiazepine-using patients and demonstrated that these changes (decrease in general intelligence and of nonverbal memory) are at least partly reversible (within a year) by discontinuing drug intake.

Sleep
https://www.ncbi.nlm...pubmed/23692988
Our findings do not support long-term effectiveness of BZDs; long-term users slept more poorly than nonusers and were even more outspoken in users of long-acting BZDs.

Tasman A; Kay J; Lieberman JA, eds. (2008). Psychiatry (3rd ed.). Chichester, England: John Wiley & Sons. pp. 1186–1200, 2603–2615. ISBN 978-0470065716.
Disrupting REM sleep by inhibiting deep stage sleep

https://www.ncbi.nlm...pubmed/20963787
Long-term benzodiazepine users were more likely to report poor sleep quality.

https://www.ncbi.nlm...pubmed/26547856
Melatonin ineffective in helping sleep during benzo withdrawal.

https://www.ncbi.nlm...pubmed/22704915
Benzodiazepines may be efficient in reducing symptoms in the short term, but evidence from this long temporal follow-up study indicates limited positive influences in the long term.

https://www.ncbi.nlm...pubmed/25145751
Sleep quality in chronic BZD/Z users significantly decreased over 1 year and was significantly worse than in nonusers at the end of this period. This study suggests that using BZD/Zs chronically does not maintain or improve sleep quality.

https://www.ncbi.nlm...pubmed/15003439
Benzos decrease REM sleep.

Elderly
https://www.ncbi.nlm...pubmed/15001721
Jackson SG, Jansen P, Mangoni A (22 May 2009). Prescribing for Elderly Patients
The long-term effects of benzodiazepines and benzodiazepine dependence in the elderly can resemble dementia, depression, or anxiety syndromes, and progressively worsens over time. Adverse effects on cognition can be mistaken for the effects of old age. The benefits of withdrawal include improved cognition, alertness, mobility, reduced risk incontinence, and a reduced risk of falls and fractures. The success of gradual-tapering benzodiazepines is as great in the elderly as in younger people. Benzodiazepines should be prescribed to the elderly only with caution and only for a short period at low doses.

https://www.ncbi.nlm...pubmed/16639148
McIntosh A, Semple D, Smyth R, Burns J, Darjee R (2005). "Depressants". Oxford Handbook of Psychiatry (1st ed.). Oxford University Press. p. 540. ISBN 0-19-852783-7.
American Geriatrics Society 2012 Beers Criteria Update Expert Panel (2012). "American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults" (PDF)
The elderly are at an increased risk of suffering from both short- and long-term adverse effects, and as a result, all benzodiazepines are listed in the Beers List of inappropriate medications for older adults.

https://www.ncbi.nlm...pubmed/26545257
The relative proportion of long-term BZD users in adult BZD users ranged from 6% to 76% (mean 24%) The estimates were higher in studies only on the elderly (47%). Long-term use involved typically steady treatment with low BZD doses. However, in elderly patients long-term BZD use and exceeding recommended doses was relatively common. Several characteristics associated with long-term use were found.

https://www.ncbi.nlm...les/PMC1934057/
Patients achieved withdrawal or reduced their dose by at least 50% after 6 and 12 months.

Seizures
https://www.ncbi.nlm...pubmed/21815323
Since the first report of benzodiazepine withdrawal seizure in 1961, many case reports have followed. Withdrawal seizures have occurred with short, medium, and long halflife benzodiazepine, if discontinued abruptly. Withdrawal seizures usually occur in patients who have been taking these medications for long periods of time and at high doses. Seizures have also been reported with less than 15 days of use and at therapeutic dosage. Almost all the withdrawal seizures reported were grand mal seizures. The severity of seizures range from a single episode to coma and death. Benzodiazepine dose tapering can be done faster in a hospital setting in high-dose abusers, but must be done more slowly in the outpatient setting in therapeutic dosage users.
Many many other articles also address this issue.

From the manufacturer drug inserts

https://dailymed.nlm...8f-880eced0239f
Xanax (generic name is alprazolam) (Pfizer)
Warnings (Pfizer)
"Even after relatively shortterm use at the doses recommended for the treatment of transient anxiety and anxiety disorder (ie, 0.75 to 4.0 mg per day), there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). "
"Seizures attributable to XANAX were seen after drug discontinuance or dose reduction in 8 of 1980 patients with panic disorder or in patients participating in clinical trials where doses of XANAX greater than 4 mg/day for over 3 months were permitted. The duration of use in the above 8 cases ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from XANAX. The risk of seizure seems to be greatest 24–72 hours after discontinuation."
Adverse Reactions
"It is suggested that the daily dosage of XANAX be decreased by no more than 0.5 mg every three days. Some patients may benefit from an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome."
Drug Abuse and Dependence
"When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of XANAX sufficient to suppress symptoms."

Also from Pfizer;
"Demonstrations of the effectiveness of XANAX by systematic clinical study are limited to 4 months duration for anxiety disorder and 4 to 10 weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient."
"Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose (eg, the patient forgets, the patient is admitted to a hospital). Therefore, the dosage of XANAX should be reduced or discontinued gradually."
"There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications."

https://dailymed.nlm...0a-41a0946f956c
Valium (generic name is diazepam) (Genentech)
Drug Abuse and Dependence
"Diazepam is subject to Schedule IV control under the Controlled Substances Act of 1970. Abuse and dependence of benzodiazepines have been reported. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving diazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence. Once physical dependence to benzodiazepines has developed, termination of treatment will be accompanied by withdrawal symptoms. The risk is more pronounced in patients on long-term therapy."
"Since the risk of withdrawal phenomena and rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage be decreased gradually."
No additional information on the Genentech website.

https://dailymed.nlm...b6-30936715d73b
Klonopin (generic name is clonazepam) (Genentech)
Drug Abuse and Dependence
"After extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed."
"Following the short-term treatment of patients with panic disorder, patients were gradually withdrawn during a 7-week downward-titration (discontinuance) period."
Dosage and Administration
"There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. Therefore, the physician who elects to use Klonopin for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient."
"Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every 3 days, until the drug is completely withdrawn."
No additional information on the Genentech website.

Ativan (generic name is lorazepam) (Valeant Pharmaceuticals)
Indication and usage
"Ativan (lorazepam) is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms.The effectiveness of Ativan (lorazepam) in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies."
Warnings
"The dependence potential is reduced when lorazepam is used at the appropriate dose for short-term treatment."
"In general, benzodiazepines should be prescribed for short periods only (e.g., 2 to 4 weeks). Extension of the treatment period should not take place without reevaluation of the need for continued therapy. Continuous long-term use of product is not recommended. Withdrawal symptoms (e.g., rebound insomnia) can appear following cessation of recommended doses after as little as one week of therapy. Abrupt discontinuation of product should be avoided and a gradual dosage-tapering schedule followed after extended therapy."
No additional information on the Valeant Pharmaceuticals website.
Oxazepam
Peak plasma time: 3 hr
Dosage
⦁ Mild/moderate anxiety - 10 to 15 mg, 3 to 4 times daily
⦁ Severe anxiety - 15 to 30 mg, 3 to 4 times daily
The half-lifee of oxazepam is 4–15 hours. Oxazepam has been shown to suppress cortisol levels.

Age of people who have Fatigue when taking Oxazepam :
0-1 2-9 10-19 20-29 30-39 40-49 50-59 60+
Fatigue 0.00% 0.00% 0.00% 9.80% 12.16% 19.26% 14.53% 44.26%
On Mar, 18, 2014: 6,810 people who reported to have side effects when taking Oxazepam are studied.

Most common Oxazepam side effects:
If people were to have side effects while taking Oxazepam, what are they:
(1) Pyrexia (fever): 613 reports. It's more common among females aged 60+ years old
(2) Asthenia (weakness): 543 reports. It's more common among females aged 60+ years old
(3) Dyspnoea (difficult or laboured respiration): 502 reports. It's more common among females aged 60+ years old
(4) Hyponatraemia (abnormally low level of sodium in the blood; associated with dehydration): 458 reports. It's more common among females aged 60+ years old
(5) Fall: 331 reports. It's more common among females aged 60+ years old, and can be severe
(6) Fatigue (feeling of tiredness): 313 reports. It's more common among females aged 60+ years old
(7) Nausea (feeling of having an urge to vomit): 279 reports. It's more common among females aged 60+ years old, and is moderate
(8) Confusion: 240 reports. It's more common among females aged 60+ years old
(9) Malaise (a feeling of general discomfort or uneasiness): 232 reports. It's more common among females aged 60+ years old.

If people were to have side effects after taking Oxazepam for a long term (> 1 year), what are they:
(1) Restlessness (not able to rest): 13 reports. It's more common among males aged 30-39 years old
(2) Jaundice (a yellowish pigmentation of the skin, the conjunctival membranes): 8 reports. It's more common among females aged 60+ years old
(3) Gait Disturbance: 5 reports. It's more common among females aged 60+ years old
(4) Hepatic failure (liver failure): 5 reports. It's more common among females aged 60+ years old
(5) Cognitive Disorder (mental health disorders affects learning, memory, perception, and problem solving): 5 reports. It's more common among females aged 60+ years old
(6) Cytolytic Hepatitis (dissolution or destruction of a liver cell): 5 reports. It's more common among females aged 60+ years old
(7) Confusional State: 5 reports. It's more common among males aged 60+ years old
(8) Urinary Retention (the inability to completely or partially empty the bladder): 4 reports. It's more common among males aged 60+ years old, and is moderate
(9) Weight Increased: 4 reports. It's more common among males aged 50-59 years old
(10) Depression: 4 reports. It's more common among males aged 30-39 years old

[fishinghat]

Prescription Meds (cont)

Effects of Discontinuation/Withdrawal

Guina, Jeffrey; Rossetter, Sarah R.; DeRHODES, Bethany J.; Nahhas, Ramzi W.; Welton, Randon S. (2015-07-01). "Benzodiazepines for PTSD: A Systematic Review and Meta-Analysis". Journal of Psychiatric Practice 21 (4): 281–303. doi:10.1097/PRA.0000000000000091. ISSN 1538-1145. PMID 26164054.

Michelini S, Cassano GB, Frare F, et al. (2016). "Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders.". Pharmacopsychiatry 29: 127–134

Gelpin, E.; Bonne, O.; Peri, T.; Brandes, D.; Shalev, A. Y. (1996-09-01). "Treatment of recent trauma survivors with benzodiazepines: a prospective study". The Journal of Clinical Psychiatry 57 (9): 390–394. ISSN 0160-6689. PMID 9746445.

Rosen, Craig S.; Greenbaum, Mark A.; Schnurr, Paula P.; Holmes, Tyson H.; Brennan, Penny L.; Friedman, Matthew J. (2013-12-01). "Do benzodiazepines reduce the effectiveness of exposure therapy for posttraumatic stress disorder?". The Journal of Clinical Psychiatry 74 (12): 1241–1248. doi:10.4088/JCP.13m08592. ISSN 1555-2101. PMID 24434093.

Wilhelm, F. H.; Roth, W. T. (1997-09-01). "Acute and delayed effects of alprazolam on flight phobics during exposure". Behaviour Research and Therapy 35 (9): 831–841. doi:10.1016/s0005-7967(97)00033-8. ISSN 0005-7967. PMID 9299803.

Matar, Michael A.; Zohar, Joseph; Kaplan, Zeev; Cohen, Hagit (2009-04-01). "Alprazolam treatment immediately after stress exposure interferes with the normal HPA-stress response and increases vulnerability to subsequent stress in an animal model of PTSD". European Neuropsychopharmacology 19 (4): 283–295. doi:10.1016/j.euroneuro.2008.12.004. ISSN 1873-7862. PMID 19167197.

Curran, H. V.; Collins, R.; Fletcher, S.; Kee, S. C. Y.; Woods, B.; Iliffe, S. (2003-10-01). "Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life". Psychological Medicine 33 (7): 1223–1237. doi:10.1017/s0033291703008213. ISSN 0033-2917. PMID 14580077.

Pary R, Lewis S (2008). "Prescribing benzodiazepines in clinical practice". Resident and Staff Physician 54 (1): 8–17.
Withdrawal symptoms or rebound symptoms in between doses mimicking or exacerbating underlying anxiety or sleep disorders, inhibiting the benefits of psychotherapy by inhibiting memory consolidation and reducing fear extinction, and reducing coping with trauma/stress and increasing vulnerability to future stress. Anxiety, insomnia and irritability may be temporarily exacerbated during withdrawal, but psychiatric symptoms after discontinuation are usually less than even while taking benzodiazepines. Fortunately, for those with benzodiazepine-induced problems, functioning significantly improves within 1 year of discontinuation.

https://www.ncbi.nlm...pubmed/16639148
https://www.ncbi.nlm...pubmed/19062773
Royal Pharmaceutical Society of Great Britain (2009). British National Formulary (BNF 57). BMJ Group and RPS Publishing. ISBN 978-0-85369-845-6.
Opinion as to the time needed to complete withdrawal ranges from four weeks to several years. A goal of less than six months has been suggested, but due to factors such as dosage and type of benzodiazepine, reasons for prescription, lifestyle, personality, environmental stresses, and amount of available support, a year or more may be needed to withdraw.

https://www.ncbi.nlm...les/PMC2943829/
Based on collective findings in this benzodiazepine withdrawal-anxiety model, we propose a functional model illustrating the changes in glutamate receptor populations at excitatory synapses during benzodiazepine withdrawal.
(Physically alters GABA receptor shape and function during withdrawal.)

https://www.ncbi.nlm.../pubmed/1675688
Protracted withdrawal syndromes from benzodiazepines.
Benzodiazepines can give rise not only to slowly reversible functional changes in the central nervous system, but may also occasionally cause structural neuronal damage.

http://www.ncbi.nlm....pubmed/25466558
This occurred independently of neuronal activity and intracellular calcium and involved GABA(A)R–gephyrin interactions, suggesting that the changes in GABA(A)R diffusion depend on conformational changes of the receptor.

https://www.ncbi.nlm...pubmed/20935233
Similar to above.

http://www.ncbi.nlm....les/PMC3494928/
Chronic BZ treatment results in allosteric uncoupling of the GABA and BZ binding sites, suggesting changes in receptor subunit composition and/or receptor function (reviewed in ref. 7). Chronic dosing of animals with BZ leads to a reduction in GABAAR synaptic inhibition (8\l "–10) and produces diverse changes in GABAAR transcripts across the brain (7). Direct comparison and interpretation of these and other studies assessing mRNA levels has been challenging due to differences in treatment paradigm (time and dose), brain regions assessed, and the BZ ligand used. Radioligand binding studies have reported mixed results, ranging from decreases to no change in CNS BZ binding sites, likely due to methodological limitations in assessing subtype-specific GABAAR changes.
(Multiple references to changes in the receptors)

https://www.ncbi.nlm...pubmed/15219633
Impaired hypothalamic-pituitary-adrenocortical (HPA) system is related to severity of benzodiazepine withdrawal in patients.

https://www.ncbi.nlm...pubmed/20140603
BDNF plasma levels decrease during benzodiazepine withdrawal in patients suffering from comorbidity of depressive disorder and benzodiazepine dependence.

https://www.ncbi.nlm...pubmed/17132385
Patients achieved withdrawal or reduced their dose by at least 50% after 6 and 12 months. Abstinence and withdrawal symptoms were also measured.

https://www.ncbi.nlm.../pubmed/7439058
Among the benzodiazepines, lorazepam seems to have a particularly high addiction potential.

https://www.ncbi.nlm.../pubmed/2880872

https://www.ncbi.nlm.../pubmed/3676860
Specificity and intensity of BDZ withdrawal symptoms were the same for those dependent upon high doses of BDZs and those dependent upon low doses, but a protracted withdrawal was only observed in low-dose BDZ-dependent patients.

http://www.ncbi.nlm..../pubmed/9063050
Protracted benzodiazepine withdrawal syndrome mimicking psychotic depression.


Withdrawal Notes

http://www.benzosupp...ey_contents.htm
See..
http://www.benzosupp...instatement.htm
29% had to go over the ORIGINAL DOSE to stabilize or could not reach a dose high enough to stabilize.

Updosing during withdrawal
http://www.benzosupp...g/up_dosing.htm
24% said it was unsuccessful.

Ashton, H. (1984). Benzodiazepine withdrawal: An unfinished story. British Medical Journal, 288, 1135-1140.

Ashton, H. (1987). Benzodiazepine withdrawal: Outcome in 50 patients. British Journal of Addiction, 82, 665-671.
These symptoms have often been temporarily alleviated by a moderate increase in dosage or the addition of another benzodiazepine, but eventually re-emerge during further chronic use and only disappear after the benzodiazepine is stopped.

http://www.smchealth...per08-12-13.pdf
If symptoms to bad stabilize dose or go up in dose for 1-2 weeks.

https://www.ncbi.nlm...d00117-0138.pdf
Small "extra dose" on any day they feel a special need for
extra help. This helps them to feel in control.

http://www.btpinfo.o...benzodiazepines
Never abruptly stop any benzodiazepine or Z drug. The shock caused by such an abrupt withdrawal is so severe that even after resumption of your drug at the previous dose, it may take weeks or months to "stabilise", and in some cases, you may never stabilise from a cold turkey withdrawal until after you have completed your reduction.


Withdrawal

Suicide
http://www.ncbi.nlm....les/PMC2047018/
Two recent studies have examined the role of benzodiazepines on actual or attempted suicide. A study examining elderly suicides in Sweden found that between 1992 and 1996, benzodiazepine hypnotics dominated drug-poisoning suicides (216 of 548, 39%) in those aged over 65 years.4 During the same time frame, a population-based cohort study in Canada found a significant association between suicide attempts and benzodiazepine usage (odds ratio = 6.2). While disinhibition and paradoxical reactions inducing suicidal impulses were considered, the authors believed that confounding by the original indication was a more likely explanation.5 Neither study reported withdrawal symptoms as a factor, although both advised examining for depression and restrictive prescribing for groups at risk of suicide.


Withdrawal Treatment

https://riordanclini...ical-rationale/
Benzodiazepine withdrawal treatment. GABA, Vitamin C and niacin.

Flumazenil
https://www.ncbi.nlm...pubmed/14578014
FLU (iv injection) immediately reversed BZD effects on balance task and significantly reduced withdrawal symptoms in comparison with oxazepam and placebo on both self-reported and observer-rated withdrawal scales. The partial agonist also reduced craving scores during the detoxification procedure. In addition, during oxazepam tapering, group B patients experienced paradoxical symptoms that were not apparent in FLU patients. Patients treated with FLU showed a significantly lower relapse rates on days 15, 23 and 30 after the detoxification week. Our data provide further evidence of FLUs ability to counteract BZD effects, control BZD withdrawal and normalize BZD receptor function.

https://www.ncbi.nlm...les/PMC4014019/
Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for 4 days significantly reduces acute benzodiazepine withdrawal sequelae.

https://www.ncbi.nlm...pubmed/26096314
The most common AEs (adverse events) in the flumazenil group were agitation and gastrointestinal symptoms, whereas the most common SAEs (significant adverse events)were supraventricular arrhythmia and convulsions.

https://www.ncbi.nlm...pubmed/27166362
This paper reports the data related to 214 subjects addicted to high doses of benzodiazepine and treated with the FLU-SSI method between 2012 and 2014. This technique is less invasive and requires less nursing intervention than intravenous infusion. Our data support FLU-SSI as a possible efficient strategy for the treatment of patients with long-term, high-dose benzodiazepine addiction

https://www.ncbi.nlm...pubmed/22596209
This small proof-of-concept study indicates that subcutaneous flumazenil infusion has excellent tolerability, efficacy and improvement on measures of psychological distress.

Cyamemazine (antihistamine)
https://www.ncbi.nlm...pubmed/22421069
Therefore, the anxiolytic efficacy of cyamemazine in benzodiazepine withdrawal can be due to a 5-HT(2AR) antagonistic activity at the cortical level.
cyamemazine vs. bromazepam
https://www.ncbi.nlm...pubmed/16243418
28 patients (total 618) in the cyamemazine group and 18 in the bromazepam group had an adverse event, including anxiety, insomnia, dry mouth and somnolence. No extra-pyramidal symptoms were reported. In conclusion, cyamemazine was comparable to bromazepam in ensuring successful benzodiazepine withdrawal and in controlling the acute benzodiazepine withdrawal syndrome. Cyamemazine may be useful to facilitate benzodiazepine withdrawal in those patients where bromazepam substitution is not appropriate.

Pregabalin (Lyrica)
"Common side effects include: sleepiness, confusion, trouble with memory, poor coordination, dry mouth, problem with vision, and weight gain.[6] Potentially serious side effects include angioedema, drug misuse, and an increased suicide risk.[6] It is moderately addictive both physically and psychologically.[1]"
Wiki
https://www.ncbi.nlm...pubmed/24532157
Our findings suggest that successful treatment of long-term BDZ use with PGB is associated with a substantial, though only partial, recovery of BDZ-compromised neuropsychological functioning, at least at a 2-month follow-up.

https://www.ncbi.nlm...pubmed/21334859
The success rates did not differ according to either the benzodiazepine of abuse or the presence of other substance use disorders. Significant and clinically relevant improvements were observed in withdrawal and anxiety symptoms, as well as in patients' functioning. At week 12, tolerability was rated as good or excellent by 90% and 83% of the clinicians and patients, respectively. Our results suggest that pregabalin is an efficacious and well-tolerated adjunctive treatment for benzodiazepine withdrawal.

https://www.ncbi.nlm...pubmed/22568872
Available evidence suggests that monotherapy with pregabalin, within the dosage range of 150 - 600 mg/d, is a promising "novel" option for the safe and efficacious relapse prevention of both AD and BD. However, its efficacy as monotherapy in the acute treatment of AD withdrawal syndrome is still controversial.

https://www.ncbi.nlm...pubmed/22545971
Between 15% and 29% of the patients were able to stop using benzodiazepines after starting pregabalin or gabapentin treatment. Psychiatric patients who started pregabalin were able to reduce the amount of benzodiazepines used by 48%, compared to only 14% among starters of gabapentin. This study shows that some patients reduced their use of benzodiazepines substantially after starting pregabalin.

Gabapentin
"Serious side effects may include an increased risk of suicide, aggressive behaviour, and drug reaction with eosinophilia and systemic symptoms.[4] It is unclear if it is safe during pregnancy or breastfeeding.[8] Lower doses should be used in people with kidney problems. Gabapentin does not affect the activity of the inhibitory neurotransmitter γ-aminobutyric acid (GABA); how it works is unclear.[4}"
Wiki
Possible links to pancreatic and other cancers (below)
http://clinicaltrial...how/NCT01138124
http://www.bioportfo...ancer-gprd.html
http://clinicaltrial...how/NCT01236053
http://www.ncbi.nlm....les/PMC3314779/

https://www.ncbi.nlm...pubmed/22545971
Between 15% and 29% of the patients were able to stop using benzodiazepines after starting pregabalin or gabapentin treatment. Psychiatric patients who started pregabalin were able to reduce the amount of benzodiazepines used by 48%, compared to only 14% among starters of gabapentin. This study shows that some patients reduced their use of benzodiazepines substantially after starting pregabalin.

[fishinghat]

Prescription Meds (cont)

Afobazole (fabomotizole)
Clinical trials have shown fabomotizole to be well tolerated and reasonably effective for the treatment of anxiety. Fabomotizole has found little clinical use outside Russia and has not been evaluated by the FDA.
https://www.ncbi.nlm...pubmed/25076752
Afobazole (5.0 mg/kg, i.p.) effectively (i) ameliorated withdrawal-induced anxiety, returning behavioral pattern in the elevated plus maze test up to levels comparable to that in vehicle-treated animals, and (ii) increased withdrawal-reduced dopamine level (+23.8%, p < 0.05) in striatum. It is suggested that afobazole, due to its multitarget receptor action, can be useful in the diazepam withdrawal-induced anxiety blockade through modulation of dopaminergic system activity.
nitric oxide synthase inhibitors

https://www.ncbi.nlm...pubmed/21857078
Administration of the non-selective NO synthase inhibitors N(G)-nitro-L-arginine (L-NOARG) and N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) significantly attenuated the withdrawal syndrome (i.e., pentetrazole-induced seizures) in diazepam-dependent mice. L-NOARG significantly suppressed hypermotility in clonazepam-dependent rats and inhibited the decrease in body weight observed after 12 h of withdrawal in chlordiazepoxide- and clonazepam-dependent rats. Moreover, a clear propensity of L-NOARG to protect benzodiazepine-dependent rats against audiogenic seizures was observed

Phenobarbital
Side effects include a decreased level of consciousness along with a decreased effort to breathe. There is concern about both abuse and withdrawal following long term use. It may also increase the risk of suicide. It is pregnancy category B or D in the United States and category D in Australia.
Wiki
Many research articles have been written on its withdrawal.

https://www.ncbi.nlm.../pubmed/1575069
https://www.ncbi.nlm.../pubmed/2147093
https://www.ncbi.nlm...pubmed/22285834
We reviewed the medical records of 310 patients treated with a 3-day fixed-dose phenobarbital taper for benzodiazepine dependence over a 5-year period between 2004 and 2009. We recorded the incidence of seizures, falls, delirium, and emergency department (ED) visits or readmission to our institution within 30 days as markers for safety; we also recorded how many patients had doses held because of sedation. The taper was well tolerated, although one quarter of the patients had at least one dose held because of sedation. There were no seizures, falls, or injuries reported. Six percent had a readmission, and 7% had an ED visit at our institution within 30 days of discharge, but only 3 patients required readmission for withdrawal symptoms. Overall, this protocol appears to be safe and effective.

βCCT
βCCT, an antagonist selective for α1GABAA receptors.
https://www.ncbi.nlm...pubmed/23149168
Acute challenge with either flumazenil (10mg/kg) or βCCt (1.25, 5 and 20 mg/kg) alleviated the diazepam withdrawal-induced anxiety. Moreover, both antagonists induced an anxiolytic-like response close, though not identical, to that seen with acute administration of diazepam. These findings imply that the mechanism by which antagonism at GABA(A) receptors may reverse the withdrawal-induced anxiety involves the α(1) subunit and prompt further studies aimed at linking the changes in behavior with possible adaptive changes in subunit expression and function of GABA(A) receptors.

https://www.ncbi.nlm...pubmed/24695241
In conclusion, the current study suggests that the role of α1-containing GABAA receptors in mediating the development of physical dependence may vary based on the effect being studied and duration of protracted treatment. Moreover, the present data supports previous findings that the lack of activity at α1-containing GABAA receptors is not sufficient to eliminate physical dependence liability of ligands of the benzodiazepine type.

https://www.ncbi.nlm...les/PMC4066304/
Variable effectiveness.

GB-115 dipeptide
https://www.ncbi.nlm...pubmed/22238979
It is established that, in 24-48 h following BZ withdrawal, GB-115 dipeptide administered in doses of 0.1 and 0.5 mg/kg, i.p., produced an anxiolytic effect in all animals, which was manifested by increasing the stay time and number of entries in EPM. In the striatum of outbred rats, GB-115 increased DOPAC (+25%) and DA (+31.6%) levels that were decreased during diazepam withdrawal syndrome. The obtained results showed the GB-115 efficiency in attenuating the anxiety caused by BZ withdrawal.

Captodiamine
Captodiame, also known as captodiamine, is an antihistamine sold under the trade names Covatine, Covatix, and Suvren which is used as a sedative and anxiolytic. It is a derivative of diphenhydramine.
Wiki
https://www.ncbi.nlm...pinewithdrawal
Analysis of the primary study criterion revealed a statistically significant difference (p < 0.0001) in the emergence of withdrawal symptoms between the two groups in favour of captodiamine at two, six and eight weeks following initiation of therapy. These results were supported by significant beneficial effects of captodiamine on the majority of secondary outcome measures. The switch to captodiamine was associated with an improvement in vigilance, which may be an advantage for the overall safety of the anxiolytic treatment, for example with regard to road safety. Discontinuation of captodiamine was not associated with the emergence of rebound anxiety.

Dothiepin (a tricyclic antidepressant not available in the USA)
https://www.ncbi.nlm.../pubmed/8730942
Not significant efficacy.

Varied treatments evaluated
https://www.ncbi.nlm...pubmed/16856084
Results support the policy of gradual rather than abrupt withdrawal of benzodiazepine. Progressive withdrawal (over 10 weeks) appeared preferable if compared to abrupt since the number of drop-outs was less important and the procedure judged more favourable by the participants. Short half-life benzodiazepine, associated with higher drop-out rates, did not have higher withdrawal symptoms scores. Switching from short half-life benzodiazepine to long half-life benzodiazepine before gradual taper withdrawal did not receive much support from this review. The role of propanolol in benzodiazepine withdrawal was unclear; adding tricyclic antidepressant (dothiepin) decreased the intensity of withdrawal symptoms but did not increase the rate of benzodiazepine abstinence at the end of the trial. Buspirone and Progesterone failed to suppress any benzodiazepine symptoms. Carbamazepine might have promise as an adjunctive medication for benzodiazepine withdrawal, particularly in patients receiving benzodiazepines in daily dosages of 20 mg/d or more of diazepam (or equivalents).

Buspirone
https://www.ncbi.nlm.../pubmed/2880872
It was concluded that buspirone does
not help benzodiazepine withdrawal and does not suppress benzodiazepine withdrawal symptoms.
https://www.ncbi.nlm...pubmed/11097963
The success rate of the taper in this study was significantly higher for patients who received imipramine (82.6%), and nonsignificantly higher for patients who received buspirone (67.9%), than for patients who received placebo (37.5%). The imipramine effect remained highly significant even after the analysis adjusted for three other independent predictors of taper success: benzodiazepine dose, level of anxious symptoms at baseline, and duration of benzodiazepine therapy.
https://www.ncbi.nlm.../pubmed/2878622
This finding supports preclinical studies indicating that buspirone has no clinically significant benzodiazepine receptor activity.
https://www.ncbi.nlm.../pubmed/2211568
Buspirone and alprazolam may be used together safely, and buspirone may be started early in the alprazolam tapering process. Thirty-six patients received placebo t.i.d. and 36 received buspirone 5 mg. t.i.d. Findings included significantly greater anxiety (as measured by the Hamilton Rating Scale for Anxiety) in the placebo group and significantly reduced manifestations of abstinence (as measured by the Abstinence Rating Scale) in the buspirone group
https://www.ncbi.nlm...pubmed/22298398
Buspirone-treated patients tended to have lower anxiety levels than placebo-treated patients.
https://www.ncbi.nlm.../pubmed/2885432
Failure of buspirone to protect against lorazepam withdrawal symptoms.

Tianeptine and Carbamazepine
https://www.ncbi.nlm...pubmed/12647454
It appears from this study that both drugs (carbamazepine and tianeptine) are comparable, safe and efficient in treating benzodiazepine withdrawal symptoms.

Carbamazepine
Common side effects include nausea and drowsiness. Serious side effects may include skin rashes, decreased bone marrow function, suicidal thoughts, or confusion. It should not be used in those with a history of bone marrow problems. Use during pregnancy may cause harm to the baby; however stopping it in pregnant women with seizures is not recommended. Its use during breastfeeding is not recommended. Care should be taken in those with either kidney or liver problems.
Wiki

https://www.ncbi.nlm.../pubmed/9005346
Compared with a gradual tapering off of benzodiazepines, abrupt withdrawal plus CBZ medication seems to be better tolerated

https://www.ncbi.nlm.../pubmed/1297907
Thirty-six outpatients aged > or = 60 yrs suffering from general anxiety disorders and benzodiazepine abuse underwent gradual discontinuation of benzodiazepine therapy in two groups, one treated with carbamazepine and one with placebo. The carbamazepine-treated group demonstrated a lower incidence of withdrawal symptoms rated according to the Physician Withdrawal Check List

https://www.ncbi.nlm.../pubmed/2929759
All patients tolerated rapid discontinuation well and none developed significant withdrawal symptoms.

https://www.ncbi.nlm.../pubmed/2021297
The results of this pilot investigation suggest that carbamazepine might have promise as an adjunctive drug therapy for the benzodiazepine withdrawal syndrome, particularly in patients receiving benzodiazepines in daily dosages of 20 mg/d or greater of diazepam equivalents.
https://www.ncbi.nlm.../pubmed/1854420
These geriatric patients experienced no major withdrawal symptoms, but mild symptoms were common. There was no correlation between dose or duration of alprazolam use and extent of withdrawal symptoms. We recommend use of this treatment regimen in a hospital setting only, where close monitoring can occur.
https://www.ncbi.nlm.../pubmed/1686406
Fundamental withdrawal symptoms (like hypersensitivity to sensory stimuli, abnormal perception of movement, depersonalisation or derealisation) were also less severe in the group treated with CBZ compared with the group not receiving that treatment. These findings support the results of previous reports indicating a therapeutical effect of CBZ in BZD withdrawal.
Widely used by detox centers.
Topiramate (Topomate)
People taking topiramate should be aware of the following risks:
⦁ Avoid activities requiring mental alertness and coordination until drug effects are realized.
⦁ Topiramate may impair heat regulation, especially in children. Use caution with activities leading to an increased core temperature, such as strenuous exercise, exposure to extreme heat, or dehydration.
⦁ Topiramate may cause visual field defects.
⦁ Topiramate may decrease effectiveness of estrogen-containing oral contraceptives.
⦁ Taking topiramate in the 1st trimester of pregnancy may increase risk of cleft lip/cleft palate in infant.
⦁ As is the case for all antiepileptic drugs, it is advisable not to suddenly discontinue topiramate as there is a theoretical risk of rebound seizures.
Wiki
There is an extensive list of side effects on Wiki and the FDA websites. Too numerous to list here.
https://www.ncbi.nlm...pubmed/12858324
A case is presented of a rapid benzodiazepine-withdrawal treated successfully with topiramate.
https://www.ncbi.nlm...pubmed/17071548
In our case of a patient with recurrent major depressive disorder, subthreshold anxiety disorder and addiction to alprazolam, topiramate appears to be efficient and safe in alprazolam withdrawal.

Alpidem
Clinical trial to obtain US FDA approval were halted in 1992 and the drug never received FDA approval. It was withdrawn from the French market by 1994 and is not approved for marketing anywhere in the world.. In 1995, Alpidem was withdrawn from the market in most of the world following reports of severe liver damage.

https://www.ncbi.nlm.../pubmed/8097214
It was concluded that alpidem is not helpful in helping patients withdrawing from a benzodiazepine withdrawal perhaps because of partial agonist properties

https://www.ncbi.nlm...pubmed/19698430
A severe WS was diagnosed in 11.1% of the patients in the alpidem group and in 31.6% of the placebo group. If not having been withdrawn from the market, alpidem could have been useful for the prevention of BZ withdrawal syndrome.

Valproate
https://www.ncbi.nlm...pubmed/22915484
Non-fatal and fatal liver failure associated with valproic acid.
Many research articles om serious side effects, some fatal for this drug.

Placebo
https://www.ncbi.nlm...pubmed/11205424
Thus, females had the highest base-line ratings and were the only group that showed a significant reduction in symptom ratings after placebo injections on the first occasion. Gender differences were also found for systolic and diastolic blood pressure.

Progesterone
is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species.
This drug has its own severe withdrawal.
https://www.ncbi.nlm.../pubmed/7604143
There was no progesterone versus placebo difference in the severity of taper withdrawal.
https://www.ncbi.nlm.../pubmed/9000261
The principal finding of the present work is that the intensity of diazepam withdrawal syndrome was significantly reduced by acute administration of progesterone

Clonidine
https://www.ncbi.nlm.../pubmed/2872826
The intensity, severity, and duration of the abstinence syndrome were not altered by clonidine at a dose sufficient to markedly reduce blood pressure and plasma free 3-methoxy-4-hydroxyphenylglycol.

https://www.ncbi.nlm.../pubmed/8577798
Finally, low doses of clonidine (0.03 mg/kg, i.p.) were shown to have anxiolytic properties and to reverse the anxiogenic effects of lorazepam on withdrawal.

Ipsapirone
https://www.ncbi.nlm.../pubmed/1676531
Ipsapirone causing true potentiation of BZ withdrawal

Not approved by the FDA yet.

Propranolol (Beta-Blocker)
https://www.ncbi.nlm.../pubmed/1971767
Those in the propranolol group suffered more severe symptoms.

https://www.ncbi.nlm.../pubmed/7910743
This paper describes pharmacological treatments that can reverse the anxiogenic response detected in animal tests when rats are withdrawn from chronic treatment with diazepam. Concurrent treatment with the calcium channel antagonist verapamil prevented this withdrawal response and the benzodiazepine-receptor antagonist flumazenil reversed the anxiogenic response and restored the system to a drug-naive state. Other treatments that reversed the anxiogenic response were the GABAB agonist baclofen, the 5-HT1A receptor agonist buspirone, and the 5-HT3 receptor antagonist (R,S)-zacopride (GABA = gamma-aminobutyric acid; 5-HT = 5-hydroxytryptamine). Both the enantiomers of zacopride contributed to this reversal. These behavioural reversals are interpreted in the light of biochemical studies showing increased 45Ca2+ flux and [3H]5-HT release from the hippocampus, during benzodiazepine withdrawal .

Hydroxyzine (Atarax) (antihistamine)
https://www.ncbi.nlm...les/PMC3598901/
Benzo use was reduced by 25% every 2 to 4 weeks.
25 mg Hydroxyzine/day.

https://www.ncbi.nlm.../pubmed/9417395
The patients had to be long term consumers (at least 3 months) of 2 mg daily of lorazepam and were withdrawn using transiently an antihistaminic anxiolytic (hydroxyzine or placebo TAD) according to 6 different procedures defining 6 parallel groups: hydroxyzine 50 mg, abrupt or progressive withdrawal; hydroxyzine 25 mg, abrupt or progressive withdrawal; placebo, abrupt or progressive withdrawal. Following this 4 week-period of withdrawal, the patients were without any treatment for a post-study follow up 2 month-period.
After a one-month period of withdrawal (under placebo or hydroxyzine) followed by a 2 month-period without any treatment, 75% patients were totally free of any drug and their level of anxiety was significantly decreased
Levels of anxiety were significantly improved in hydroxyzine 50 mg group and in hydroxyzine 25 mg group but not in placebo group. Withdrawal symptoms between D0 and D28 were improved only in hydroxyzine 50 mg group and the number of side effects was significantly improved in both the hydroxyzine (25 et 50 mg) groups but not in placebo group.
When a patient is engaged to be withdrawn from of a lorazepam long term treatment, it can therefore be proposed as a support a transient prescription of hydroxyzine 25 mg TAD to markedly anxious patients and of hydroxyzine 50 mg TAD to patients presenting a withdrawal symptomatology.

https://www.ncbi.nlm...pubmed/18379511
The study aimed at investigating of efficacy of hydroxyzine (atarax) as a substitutive drug used in case of benzodiazepine tranquilizers (BDT) withdrawal in patients who received BDT for more than 3 months. Fifty-nine patients with protracted chronic anxiety-phobic disorders were divided into 2 groups: in the first (main) one, BDT were withdrawn at once with the following assignment of substitutive therapy with atarax and in the second (control) group the withdrawal was continuous during 14 days with the simultaneous assignment of a substitutive placebo therapy. In the first group (resumed the BDT therapy because of worsening of their state 23,3% patients finished their participation in the study ahead of time as compared to 65,6% of those in the control group. The Hamilton Anxiety Scale scores were more reduced in the main group than in the control one. The results obtained suggest that atarax is worth to be used as a substitutive drug for BDT.
Z Drugs

Definition - Z-drugs are a group of nonbenzodiazepine drugs with effects similar to benzodiazepines, which are used in the treatment of insomnia, and most of whose names start with the letter "Z". Some Z-drugs may have advantages over benzodiazepines. (Wiki)
Eszopiclone (Lunesta) (Zopiclone )
Zaleplon (Sonata).
Zolpidem (Ambien)

Benzodiazepines and Z Drugs

https://www1.ghc.org...benzo-zdrug.pdf
Benzodiazepine and Z-Drug Safety Guideline
This guidance document is an excellent over view of these two drug groups. It explains how the Z-Drugs act just like benzos, a little less effective on anxiety and a little more effective on sleep. They are just as addictive, severe withdrawal and because their action is the same as benzos they should not be taken with benzos as it increases the rate of addictiveness and severity of withdrawal.

https://www.ncbi.nlm...pubmed/25474727
The risk to develop BZD/z-drugs dependence is significantly associated with psychiatric history and with the quantity of BZD/z-drugs that is taken.

https://www.ncbi.nlm...pubmed/24774720
Dependence on benzodiazepines (BZDs) or Z-drugs (zolpidem, zopicline and zaleplon) is a common clinical phenomenon.
https://www.ncbi.nlm...pubmed/18505619
There were no significant differences in patients' perceptions of efficacy or side-effects reported by those on Z drugs compared to patients taking benzodiazepines. Side-effects were commonly reported, which may have contributed to a high proportion of responders, particularly patients on Z drugs who were wishing to stop, or who had previously tried to stop taking this medication. Reported prescribing practices were often at variance with the licence for short-term use.
About half of those with sleep problems seek medical help, which often involves a prescription of hypnotic drugs including benzodiazepines like temazepam, or Z drugs such as zopiclone, zolpidem, or zaleplon. Most hypnotic prescribing takes place in primary care, and drug treatments may be inappropriately prescribed for 4 weeks or longer in up to 50% of new prescriptions.
No significant differences between Z drugs and benzodiazepines were found in respect of perceived benefits or adverse effects, including withdrawal or dependence.

https://www.nice.org...522015122913515
Guidance document from NICE (National Institute for Health and Care Excellence, UK)on the use of Benzos and Z-drugs.
"There is no firm evidence of differences in the effects of zaleplon, zolpidem, zopiclone and the shorter-acting benzodiazepines."
"If treatment with one of these hypnotic medicines does not work, the doctor should not prescribe one of the others."
A drug used to induce sleep is described as a 'hypnotic'.
The Summary of Product Characteristics (SPC) specifies that treatment (with Zaleplon) should be as short as possible with a maximum duration of 2 weeks. The SPC states that the duration of treatment (with Zolpidem) should usually vary from a few days to 2 weeks with a maximum of 4 weeks, including tapering off where appropriate. The SPC also states that the duration of treatment (with Zopiclone) should be 2–5 days for transient insomnia and 2–3 weeks for short-term insomnia.
http://www.nhsgrampi...zo_649_1014.pdf
In practice short-term prescribing should be limited to a maximum of two weeks as signs of psychological and physical dependence can develop if prescribed for longer periods.

*Z- drugs which include zaleplon, zolpidem and zopiclone are non benzodiazepine hypnotics, they carry the same risks and dependence problems as benzodiazepines.

Z drugs are indicated only for the short term management of severe insomnia that interferes with normal daily life, and should be prescribed for short periods of time only (up to two to four weeks for Zopiclone, Zolpidem and up to two weeks for Zaleplon).

There is no justification for prescribing more than one benzodiazepine or Z-drug concurrently, except during the period of conversion.

If the patient is struggling with symptoms of withdrawal, halt the reduction and maintain the current dose until symptoms improve. Increases in dose are to be discouraged.

http://www.setrust.h...and_Z_Drugs.pdf
There is no significant difference in adverse effects between benzodiazepines and zopiclone and not enough data to choose one over the other. There is no significant difference in sleep latency between benzodiazepines and zopiclone. The risk of hip fracture is as likely with z drugs as with other benzodiazepines.

They offer no clinically significant advantages over benzodiazepines

Only use for the short-term treatment of severe anxiety or insomnia (anxiety maximum of 4 weeks, insomnia maximum of 10 nights)

[juli]

Hi there!  I just wanted to add that I found neurofeedback to be super helpful when I was going through withdrawl.  I went twice a week and it kind of "fixed my brain" a bit and helped a lot with the anxiety.  I ended up needing 28 sessions.

Juli

[fishinghat]

Juli, thanks for the input. That section is soon to arrive.

[fishinghat]

Prescription Meds (cont)

Ambien (Zolpidem)
https://dailymed.nlm...96-8702a28e6e76
Note - The following is from the drug insert supplied with Ambien (Manu; Sanofi-aventis) and is an example of a typical drug insert for Z-Drugs. See above website for inserts from other Z-drugs and manufacturers.

"Sleep-driving" and other complex behaviors while not fully awake. Risk increases with dose and use with other CNS depressants and alcohol. Immediately evaluate any new onset behavioral changes.
Depression: Worsening of depression or, suicidal thinking may occur. Prescribe the least amount of tablets feasible to avoid intentional overdose.
Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation
Observed reactions include anaphylaxis and angioedema.
Additive effects occur with concomitant use of other CNS depressants (e.g. benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of AMBIEN CR and concomitant CNS depressants should be considered.
Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including AMBIEN CR. Some of these changes included decreased inhibition (e.g. aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation and depersonalization. Visual and auditory hallucinations have been reported.
Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with "sleep-driving", patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may also occur.
In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides), have been reported. Suicidal tendencies may be present in such patients and protective measures may be required.
Zolpidem can cause drowsiness and a decreased level of consciousness, which may lead to falls and consequently to severe injuries. Severe injuries such as hip fractures and intracranial hemorrhage have been reported.
Data from a clinical study in which selective serotonin reuptake inhibitor- (SSRI-) treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction.
Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.

https://www.ncbi.nlm...pubmed/14519173
Zolpidem and zopiclone can cause dependence.

[fishinghat]

Prescription Meds (cont)

https://www.ncbi.nlm...pubmed/24531568
We found that subchronic zolpidem and diazepam administration produced ...increased anxiety-like behaviors 1 day after drug termination.
https://www.ncbi.nlm...pubmed/26776243
This study demonstrated a significant association between using zolpidem and suicide or suicide attempt in people with or without comorbid psychiatric illnesses.
https://www.ncbi.nlm...pubmed/22444504
In 83.5% of cases, psychoactive substances other than zolpidem were detected, most commonly antidepressants (46.2%), benzodiazepines (35.2%), opioids (26.4%), and alcohol (39.6%). In summary, zolpidem was a factor contributing to death in a large proportion of cases, predominately involving drug toxicity and suicide.
https://www.ncbi.nlm...pubmed/24931450
Results revealed medium effect sizes for zopiclone and zolpidem on measures of verbal memory. An additional medium effect size was observed for zolpidem on attention. Finally, smaller effect sizes were observed for zolpidem speed of processing and for zopiclone on working memory. It is clear from these data that the use of a single dose of the z-drugs in healthy adults as measured in the morning following the exposure does produce a specific rather than a generalized negative effect on cognitive function. However, there were only enough studies to evaluate the individual cognitive effects of the zolpidem and zopiclone medications; the specific effects of zaleplon and eszopiclone cannot be ascertained because only one study met the inclusion and exclusion criteria for the review.
https://www.ncbi.nlm...les/PMC3906775/
This case showed that zolpidem can exert abuse capability, euphoric mood, tolerance, and withdrawal syndrome.
http://www.benzo.org.uk/ashtonad.htm
Do not change type or dose of antidepressants while withdrawing from a benzo. Wait for 4 weeks or more after withdrawal complete to change.

Lunesta

“Lunesta is now available in a generic form in the United States as of May 2014. On May 15, 2014 US FDA asked for lowering starting dose of drug Eszopiclone (Lunesta) from 2 Mg to 1 Mg after it was observed in a study that even after 8 hours after taking drug in night, some patients were not able to cope up with their next-day activities like driving and other activities that require full alertness.”

Lunesta is slightly effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint. Kirsch et al. found the benefit over placebo to be of questionable clinical significance. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produce a reasonably large clinical response.

Use of benzodiazepines and similar benzodiazepine-like drugs such as eszopiclone may lead to physical and psychological dependence.

Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like drugs for a few weeks. Lunesta was studied for up to 6 months in a group of patients which showed no signs of tolerance or dependence in a study funded and carried out by Sepracor.

Lunesta acts on benzodiazepine binding site situated on Gaba receptors as an agonist.


In a 2009 article in the New England Journal of Medicine, "Lost in Transmission — FDA Drug Information That Never Reaches Clinicians", it was reported that the largest of three Lunesta trials found that compared to placebo Lunesta "was superior to placebo" while it only shortened initial time falling asleep by 15 minutes on average. "Clinicians who are interested in the drug’s efficacy cannot find efficacy information in the label: it states only that Lunesta is superior to placebo. The FDA’s medical review provides efficacy data, albeit not until page 306 of the 403-page document. In the longest, largest phase 3 trial, patients in the Lunesta group reported falling asleep an average of 15 minutes faster and sleeping an average of 37 minutes longer than those in the placebo group. However, on average, Lunesta patients still met criteria for insomnia and reported no clinically meaningful improvement in next-day alertness or functioning."[19]
All of the above from Wikipedia

http://www.ncbi.nlm....pubmed/24882900

http://www.ncbi.nlm....pubmed/23251857
Lunesta less effective in patients with depression and anxiety
http://www.ncbi.nlm....pubmed/23198272
Lunesta induced psychosis.

http://www.ncbi.nlm....pubmed/23126273
Sleepiness extends to daytime.

http://www.ncbi.nlm....pubmed/23063301
Effectiveness

http://www.ncbi.nlm....pubmed/22731653
Helps with sleep with those with psych disorders.

http://www.ncbi.nlm....pubmed/21540024
stimulates the hypothalamo-pituitary-adrenal axis

http://www.ncbi.nlm....pubmed/21367352
Effective on PTSD patients.

http://www.ncbi.nlm....pubmed/20408925
Makes anti-depressants more effective.

http://www.ncbi.nlm....pubmed/20153782
Effects on REM sleep.
-----------------------------------------------------------------------------------------------------------

[fishinghat]

Effects of Cymbalta on the Body
Hypothyroidism. It is a common side effect of the use of ssri/snri antidepressants. The medicine inserts that come with antidepressants nearly always warn of the risk of developing hypothyroidism and/or liver damage. These chemicals (medicines) are often suppressive to the function of these tissues. It is standard procedure that a psychiatrist will stop the use of ssri/snri for 3 months to allow the thyroid to recover (which it almost always does unless actual damage is done to the tissue). At that point a different ssri/snri will be used to see if it can be used without effect on the thyroid. Zoloft is the one that apprears to have the best record. It is important to note that it is essential to consider any radiological testing that may have been done around the same time. It has been shown that around 30% of the abdominal cat scans use enough contrast iodine to produce hypothyroidism. It is usually asymptomatic and does return to normal within a 6 to 9 month period. A simple 24 hour urine sample can show if iodine toxicity (from cat scans/radiation imaging) is the source of the hypothyroidism.
FH - NO good endocrinologist would put you on thyroid medicine immediately after blood tests suggesting hypothyroidism unless you are very symptomatic and in despite need for help. I was diagnosed with HypoT after being on Cymbalta. My primary care dr said I would have to be on thyroid medicine for life. I went to my endocrinologist and he threw a fit. I was informed, but was already aware, that many conditions can causes hypoT blood test results including the radiation, aspirin usage and some of the other nsaids, many other medicines, as well as infections. All clear when the causative agent is removed. Even a seafood diet and/or heavy iodine salt usage can cause this.
http://www.cymbaltaw...tion/?hl=helped
List of AD that can cause thyroid issues.
http://www.cymbaltaw...rove#entry46513
Hypothyroidism and depression information.

Antidepressants which effect thyroid levels
reboxetine - TSH reduced and T4 increased.
sertraline - TSH increased and T4 reduced.
https://www.ncbi.nlm.../?term=18262705

sertraline and fluoxetine showed reductions in TSH,T3 and T4 levels.
https://www.ncbi.nlm.../?term=15486607

Fluoxetine decreased T3 and T4, increased TSH
https://www.ncbi.nlm...d/?term=6413229

Do not treat with thyroid hormones if hypothyroidism is asymptomatic.
These are often accompanied by findings such as low blood pressure, low blood glucose, low sodium, high potassium, and high calcium.
As a matter of fact all of these parameters were normal for me therefore it is unlikely it is due to sertraline.
Reference Range(s)
70-500 µg/24 h
93-1,125 mcg/specimen
Iodine defeciency - less than 50 μg/L
Table 2. Median Population Urinary Iodine Values and Iodine Nutrition
MEDIAN URINARY IODINE CONCENTRATION (μg/L) CORRESPONDING IODINE INTAKE (μg/day) IODINE NUTRITION
<20 <30 Severe deficiency
20-49 30-74 Moderate deficiency
50-99 75-149 Mild deficiency
100-199 150-299 Optimal
200-299 300-449 More than adequate
>299 >449 Possible excess
[From WHO, UNICEF and ICCIDD 2001 Assessment of the Iodine Deficiency Disorders and monitoring their elimination. A guide for programme managers. WHO publ., Geneva. WHO/NHD/01.1]
1 Microgram per liter [µg/l]

= 0.000 1 Milligram per deciliter [mg/dl]


https://www.ncbi.nlm...pubmed/22450350
Escitalopram-induced subclinical hypothyroidism. A case report.

https://www.ncbi.nlm...pubmed/20851281
Reversible escitalopram-induced hypothyroidism.

https://www.ncbi.nlm...pubmed/17874352
Reversible paroxetine-induced symptomatic hypothyroidism.

https://www.ncbi.nlm...pubmed/11054982
Depressed patients should be screened for hypothyroidism. In hypothyroid patients, depression may be more responsive to a replacement regimen that includes T3 rather than T4 alone. Therefore, inclusion of T3 in the treatment regimen may be warranted after adequate trial with T4 alone.

https://www.ncbi.nlm.../pubmed/7779834
Effects of long term treatment with sertraline (Zoloft) simulating hypothyroidism in an adolescent.
And many more articles.

ssri/snri replacement is a viable option.

https://www.drugs.com/pro/effexor.html
Side effects
"Endocrine system—Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis."

https://dailymed.nlm...54-00144ff88e88
The same is mentioned in the section on 'adverse reactions' in the drug insert for Effexor.


http://www.ehealthme...hypothyroidism/
65,121 people reported to have side effects when taking Effexor.
Among them, 420 people (0.64%) have Hypothyroidism

http://www.ehealthme...hypothyroidism/
An FDA supported website.
84,701 people reported to have side effects when taking Cymbalta.
Among them, 292 people (0.34%) have Hypothyroidism

https://dailymed.nlm...f2-c185fbad64ba
Drug insert. (Cymbalta)
Endocrine Disorders — Infrequent: hypothyroidism.

-------------------------------------------------------------------------------------------------------

[fishinghat]

Effects of Cymbalta on the Body (cont)

Tinnitus
Partial list of entries on this site referring to tinnitus.
You will see a pattern, the faster the withdrawal the worse the tinnitus and the longer lasting the occurance. It also seems to be more common in those on the generic form.
My website search showed 6 pages of entries, too many to list here.
Medical journal info to follow.

Lady Nancy 4/16/13 and many many other times. An excert from section 5.7 of the drug insert for Cymbalta.
"During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe."

Must read...
http://www.cymbaltaw...om/?hl=tinnitus

Things that list tinitus as a common symptom during dicontinuation;
Benzos
Coffee
Alcohol
Opium
SSRI
SNRI
Bath Salts
Dilantin and more.
---------------------------------------------------------------------------------------------------------
Restless Leg Syndrome
(Synopsis from PubMed)
Causes
Research and brain autopsies have implicated both dopaminergic system and iron insufficiency in the The substantia nigra plays an important role in reward, addiction, and movement and is composed of dopaminergic neurons. This area is one of the primary areas for the production of dopamine. Iron is an essential cofactor for the formation of L-dopa, the precursor of dopamine and adrenaline.
Magnesium deficiency.
Magnesium deficiency showed important disorders of sleep organization, agitated sleep with frequent periods of nocturnal awakenings, increase of the durations and percentages of light sleep, a decrease of duration and percentage of deep sleep, a decrease of duration and percentage of REM sleep caused by magnesium deficiency with the disappearance in the REM sleep in some.

Iron Deficiency
The most commonly associated medical condition is iron deficiency (specifically blood ferritin below 50 µg/L), which accounts for just over 20% of all cases of RLS. Normal blood levels are 30-300 ng/mL for males and 15-200 ng/mL for females. Studies using cerebrospinal fluid, magnetic resonance imaging, ultrasound determination of iron and autopsy tissue have implicated a primary role for brain (substantia nigra) iron insufficiency in restless legs syndrome (RLS). Ferritin can deliver iron to multiple organs, including the brain. The data clearly show changes in iron status affect dopaminergic activity. The proposed etiology of RLS is the central dopaminergic dysfunction, based on the benefits of dopamine agonists and exacerbation of RLS symptoms by dopaminergic antagonists.

Iron is most available to the body when chelated to amino acids - iron in this form is ten to fifteen times more bioavailable than any other, and is also available for use as a common iron supplement. Often the amino acid chosen for this purpose is the cheapest and most common amino acid, glycine, leading to "iron glycinate" supplements. RDA for iron varies considerably based on age, gender, and source of dietary iron (heme-based iron has higher bioavailability).
Iron uptake is tightly regulated by the human body, which has no regulated physiological means of excreting iron. Only small amounts of iron are lost daily due to mucosal and skin epithelial cell sloughing, so control of iron levels is mostly by regulating uptake.Regulation of iron uptake is impaired in some people as a result of a genetic defect that maps to the HLA-H gene region on chromosome 6. In these people, excessive iron intake can result in iron overload disorders, such as hemochromatosis. Many people have a genetic susceptibility to iron overload without realizing it or being aware of a family history of the problem. For this reason, it is advised that people do not take iron supplements unless they suffer from iron deficiency and have consulted a doctor. Hemochromatosis is estimated to cause disease in between 0.3 and 0.8% of Caucasians.
Certain medications may worsen RLS in those who already have it, or cause it secondarily. These include: any antidepresssants(SSRIs).
Genetics
More than 60% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.
Six genetic loci found by linkage are currently known and are listed below.
12q,14q, 9p, 20p, 2p and 16p12.1.
Four genes, MEIS1, BTBD9, PTPRD and MAP2K5, were found to be associated to RLS.
Effects
Sleep - For 60%–80% of patients with RLS, sleep disturbance is their most distressing symptom. For example, impact on patients’ daytime cognitive abilities, patients report reduced concentration and attention, increased daytime sleepiness, and mood disturbance. Studies have indicated that the symptoms of RLS precede those of depression or anxiety, and others relate the severity of mood symptoms to the severity of RLS symptoms. For some patients, the effects on mental health may be so pronounced as to reach the diagnostic criteria for major depressive disorder or generalized anxiety disorder

Several studies have shown an association between the symptoms of RLS and worse mental health. The authors concluded that the presence of RLS symptoms “was probably the major determining factor for the anxiety and depression scores, with higher scores correlating with more severe RLS”.

Diagnosis

Serum ferritin levels are measured in patients as part of the iron studies workup for anemia and for restless leg syndrome. The ferritin levels measured have a direct correlation with the total amount of iron stored in the body including cases of anemia of chronic disease.
Normal blood levels are 30-300 ng/mL for males and 15-200 ng/mL for females.
Treatment
Patients with RLS and prominent anxiety symptoms may require treatment with an anxiolytic in addition to dopaminergic therapy for the RLS symptoms. The benzodiazepines have been used in the treatment of RLS. Their efficacy depends mostly on reducing insomnia, rather than managing the motor and sensory symptoms of RLS. These drugs may be useful in the management of RLS and anxiety, though there are concerns about the long-term use of these agents and patients require monitoring for dependency and declining efficacy.
Iron supplements - People with RLS should have their ferritin levels tested; ferritin levels should be at least 50 µg for those with RLS. Oral iron supplements, taken under a doctor's care, can increase ferritin levels. For some people, increasing ferritin will eliminate or reduce RLS symptoms. A ferritin level of 50 µg is not sufficient for some sufferers and increasing the level to 80 µg may greatly reduce symptoms. However, at least 40% of people will not notice any improvement. It is dangerous to take iron supplements without first having ferritin levels tested, as many people with RLS do not have low ferritin and taking iron when it is not called for can cause iron overload disorder, potentially a very dangerous condition.
RDA – 8 mg/day; UL 45 mg/day One used 200 mg ferrous sulfate 3 times per day, which equals 73.5 mg iron 3 times per day or 225 mg/day. An additional study used 7 mg of iron/day. They used iron succinylate or bisglycinate
Clonidine - Patients subjectively reported improvement in leg sensations and motor restlessness while receiving clonidine (0.05 mg/day). Sleep onset occurred faster with clonidine (12 minutes) compared with placebo (30 minutes) and baseline (47 minutes). Adverse findings with clonidine treatment included decreased REM sleep in the clonidine group (4%) compared with placebo (16%) and baseline (16%) and increased REM delay in the clonidine group (195 minutes) compared to the placebo (70 minutes) and baseline groups (89 minutes) There was a nonstatistical trend toward an increase in stage 3 and 4 sleep and a decrease in motor activity. Clonidine may be an effective treatment for RLS patients who don't have large numbers of sleep-disrupting periodic limb movements but have delayed sleep onset due to leg sensations and
An additional double-blind study was conducted in 20 patients with renal failure and symptoms of restless legs. 10 patients were treated with 0.075 mg clonidine twice daily and 10 received placebo. Three days after starting therapy. the clonidine-treated group complete relief of symptoms was noted in 9 out of 10 patients.

Gabapentin - Gabapentin, an analog of gamma-aminobutyric acid, was compared with L-dopa in a small, open-label study involving patients with RLS secondary to renal disease. After 4 weeks, both treatments improved the symptoms of RLS. Gabapentin produced significant improvements compared with baseline on three of the eight SF-36 domains. Gabapentin produced adverse events of malaise (feeling bad) and somnolence (drowsiness); but resulted in no patient withdrawal.

Magnesium/Calcium– RDA 400 mg/day Serum levels should be between .7 and 1 mmoles/L. Studies used 400 – 800 mg/day. (avg. 600 mg/day; 6 tablets) Special note - Amino Acid Magnesium most readily absorbed form of magnesium and most tolerated by the gi tract.
Studies recommend using 600 to 1,000 mg calcium with the magnesium. (800 mg/day avg.; ) RDA 1,000 mg/day, UL 2500 mg/day. The individual must allow for dietary intake. As calcium and magnesium compete in the blood system you should also have your serum calcium and magnesium nmonitored every 6 months.

Magnesium availability different Mg-sources
Mg-source Mg-content % Rel. Biological value % Rel. Available Mg g/kg
Mg-Chloride 12 89 107
Mg-Hydroxide 36 99 356
Mg-Phosphate 26 85 221
Mg-Ca-Phosphate 9 91 82
Mg-Ca-Na Phosphate 5 94 47
Mg-Oxide, granular 51 61 311
Mg-oxide, powder 51 84 428
MG-Sulphate 10 96 96
Source: EMFEMA 2002
Folic Acid – Recommended to be taken, no research to back this. Use folic acid at 4 – 10 mg/day.
http://www.cymbaltaw...rls/#entry72695
Detailed information on Restless Leg Syndrome
----------------------------------------------------------------------------------------------------------

[fishinghat]

Effects of Cymbalta on the Body (cont)

Cymbalta and Pregnancy
http://www.ncbi.nlm....pubmed/23471302
No significant effect on fetus.

http://www.ncbi.nlm....pubmed/21359876
Low amount of cymbalta across placenta and in lactation.

http://www.ncbi.nlm....pubmed/23218163
Text not available.

http://www.ncbi.nlm....pubmed/23873363
No effects on new born health.

http://www.ncbi.nlm....pubmed/19809008
No effect on fetus, newborn at birth or during lactation.

http://www.ncbi.nlm....les/PMC3590601/
List what the negative out comes are.

http://www.ncbi.nlm....pubmed/25171134
Increase risk of club foot with ssri.

http://www.bmj.com/c.../bmj.g4835.long
SSRI increase risk of autism in new borns.

https://www.ncbi.nlm...pubmed/25551238
Little transferred to infant.

Duloxetine withdrawal syndrome in a newborn
http://cpj.sagepub.c...52/10/976.short
Clinical presentation and management of neonatal abstinence syndrome
http://www.dovepress...hp?fileID=19621

Use of selective serotonin reuptake inhibitors during pregnancy
http://contemporaryo...nancy?page=full

Neonatal paroxetine withdrawal syndrome
http://www.ncbi.nlm....les/PMC1721229/
Four term neonates presented with symptoms such as jitteriness and necrotising enterocolitis after paroxetine exposure in utero.

The use of psychotropic medication during pregnancy: how about the newborn?
http://www.ncbi.nlm....les/PMC3770341/

http://www.cymbaltaw...tion#entry40047
Info on Cymbalta and pregnancy
Additional Information
Medical journal articles on Prozac and pregnancy...
http://www.aafp.org/...0515/p1211.html
(aafp medical Journal article)
Risks (see Table 1)

http://www.nejm.org/...199610033351402
(New England Journal of Medicine)
Women who take fluoxetine during pregnancy do not have an increased risk of spontaneous pregnancy loss or major fetal anomalies, but women who take fluoxetine in the third trimester are at increased risk for perinatal complications.

https://www.ncbi.nlm...pubmed/23660045
RESULTS:
Twenty-one studies met the inclusion criteria. The odds ratio for major malformations associated with maternal fluoxetine use in cohort studies was 1.12 (95% CI 0.98 to 1.28). The studies included were homogeneous. Fifteen cohort studies evaluated cardiac malformations and yielded an overall odds ratio of 1.6 (95% CI 1.31 to 1.95). These studies also were homogeneous. In contrast, two case-control studies assessing cardiac malformations yielded a combined odds ratio of 0.63 (95% CI 0.39 to 1.03).
CONCLUSION:
The apparent increased risk of fetal cardiac malformations associated with maternal use of fluoxetine has recently been shown also in depressed women who deferred SSRI therapy in pregnancy, and therefore most probably reflects an ascertainment bias. Overall, women who are treated with fluoxetine during the first trimester of pregnancy do not appear to have an increased risk of major fetal malformations.

https://www.ncbi.nlm...pubmed/27018763
Perinatal Fluoxetine Exposure Impairs the CO2 Chemoreflex. Implications for Sudden Infant Death Syndrome.
We concluded that prenatal-perinatal fluoxetine treatment impairs central respiratory chemoreception during postnatal life. These results are relevant in understanding the pathogenesis of respiratory failures, such as sudden infant death syndrome, associated with brainstem serotonin abnormalities and the failure of respiratory chemoreflexes.

https://www.ncbi.nlm...les/PMC4909759/
In conclusion, fluoxetine has marginal effects on the timing of developmental stages in embryos, but induces expression and secretion of several proteins in a manner that depends on dose. For these reasons, and in line with current guidelines, the lowest possible dose of SSRI should be used in pregnant women who need to continue treatment.

https://www.ncbi.nlm...pubmed/25948853
Serotonin syndrome in a breast-fed neonate.
A late preterm presented with tachypnoea, jitteriness, irritability and low grade fever. Blood gas showed a compensated metabolic acidosis. His mother was taking the selective serotonin reuptake inhibitor (SSRI) fluoxetine, 60 mg/day, and he was exclusively breast-fed. The baby's serum level of fluoxetine on day 8 was within the adult therapeutic range and his symptoms were ascribed to fluoxetine toxicity. On changing to formula feeds, his symptoms resolved. SSRIs are commonly administered during pregnancy, but SSRI toxicity in infants is rarely reported. It is possible that this condition is under diagnosed or, alternatively, misdiagnosed as SSRI withdrawal in breast fed infants whose mothers are on SSRIs. There is limited research looking at serotonin excess in neonates, making case reports such as this important in our learning. Increased awareness may prompt more frequent measurements of blood levels in breast-fed infants whose mothers are on SSRIs.

https://www.ncbi.nlm.../pubmed/8474204
Our study suggests that the use of fluoxetine during embryogenesis is not associated with an increased risk of major malformations. Women exposed to both fluoxetine and tricyclic antidepressants tended to report higher rates of miscarriage; further studies will be needed to confirm this observation and to separate the effects of the psychiatric condition from the associated drugs. Long-term studies will be warranted to rule out potential developmental teratology of fluoxetine, which affects a central nervous system neurotransmitter.


https://www.ncbi.nlm.../pubmed/8414864
Fluoxetine hydrochloride (Prozac) toxicity in a neonate.
A case of fluoxetine toxicity in a newborn of 38 weeks' gestation has been presented. The total drug concentration in cord blood was 80 ng/mL. The fluoxetine level, 26 ng/mL, is below the adult therapeutic level; the norfluoxetine cord blood level, 54 ng/mL, is at the adult therapeutic level. At 96 hours the fluoxetine level was not measurable and the norfluoxetine level was 55 ng/mL. The parent compound is fluoxetine, which is metabolized in the liver to norfluoxetine. The half-life of fluoxetine is 2 to 3 days, and that of norfluoxetine is 7 to 9 days. Interestingly, in our patient the fluoxetine was absent in the blood at 4 days, but norfluoxetine was present. The most common side effects of Prozac in adult patients involve primarily the central nervous system and include nervousness, tremor, jitteriness, and occasionally seizures. Central nervous system symptoms were most prominent in this newborn. He also had an increased heart rate. Cardiovascular side effects are less prominent in adults who are taking Prozac. The neonate in this case was asymptomatic at 96 hours of age, indicating that the parent compound, fluoxetine, may be the active part of the drug and side effects may be caused by the parent compound.

Autism research and Antidepressants
http://www.huffingto...4b0e292150f72e3

http://archpedi.jama...ticleid=2476187
------------------------------------------------------------------------------------------------------------

[fishinghat]

Effects of Cymbalta on the Body (cont)

Cymbalta and the Heart
https://www.ncbi.nlm...pubmed/27130441
Differential inhibition of cardiac and neuronal Na(+) channels by the selective serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine.

https://www.ncbi.nlm...pubmed/23422380
"In conclusion, in healthy adults exposed to DLX (Cymbalta) or ESC, no clinically significant effects on HRV (heart rate variability) were observed."

https://www.ncbi.nlm...pubmed/22163139
Abstract
Herein, we report the case of a 59-year-old woman whose takotsubo cardiomyopathy was temporally associated with the titration of duloxetine. The duloxetine therapy was subsequently discontinued, and the patient's left ventricular function recovered completely 1 month after the index event. The purpose of this report is to alert clinicians to a possible association between SNRI medications and takotsubo cardiomyopathy.

https://www.ncbi.nlm...pubmed/18728105
Duloxetine-associated tachycardia
"Clinicians should be aware of the possibility of clinically significant tachycardia in patients receiving duloxetine, even in low doses."

https://www.ncbi.nlm...pubmed/18445706
Heart failure worsening and exacerbation after venlafaxine and duloxetine therapy.
"Use of drugs that increase serum norepinephrine levels, such as the SNRIs, may be potentially deleterious in individuals with unstable or advanced HF. These medications should be avoided or used with caution and monitored regularly in this patient population."

https://dailymed.nlm...f2-c185fbad64ba
"Cardiac Disorders — Frequent: palpitations; Infrequent: myocardial infarction and tachycardia. "
Post Marketing reports - supraventricular arrhythmia,

http://www.cymbaltaw...tion#entry70794
Information on Heart conditions and Cymbalta
------------------------------------------------------------------------------------------------------------

[fishinghat]

Effects of Cymbalta on the Body (cont)

Cymbalta and High Blood Pressure

http://dailymed.nlm....?archiveid=1526
This is a document from Eli Lilly that in it it links high BP to Cymbalta.

http://www.nlm.nih.g...ds/a604030.html
Medline plus includes a warning about high BP as well. Medline plus is a service of the Federal government.

http://www.ehealthme...pressure - high
This article is from ehealth. It monitors reported side effects to the FDA and other sites. Over 5% of the users of cymbalta report high bp.

http://www.ncbi.nlm....pubmed/16303903
http://www.ncbi.nlm....les/PMC3661232/
http://www.ncbi.nlm....les/PMC2646646/
http://www.ncbi.nlm....les/PMC3004624/
http://www.ncbi.nlm....les/PMC3437646/
Research articles documenting elevation of bp by Cymbalta.

http://www.fda.gov/d...y/ucm088579.pdf
http://www.accessdat...0/022516lbl.pdf
FDA warns of risk of high blood pressure. Second one includes a black box warning from 2010 on elevated BP.
------------------------------------------------------------------------------------------------------------

[fishinghat]

Effects of Cymbalta on the Body (cont)

Cymbalta's Damages/Effects

Introduction - Cymbalta is a seratonin norepinephrine reuptake inhibitor (SNRI). It is mostly prescribed for major depressive disorder, generalized anxiety disorder, fibromyalgias and neuropathic pain. Duloxetine failed to receive US approval for stress urinary incontinence amid concerns over liver toxicity and suicidal events; however, it was approved for this indication in the UK, where it is recommended as an add-on medication in stress urinary incontinence instead of surgery.
Serotonin (5HT) is primarily found in the gastrointestional tract (GI tract), blood platelets, and the central nervous system (CNS). It is popularly thought to be a contributor to feelings of well-being and happiness. Serotonin action is terminated primarily by uptake of 5-HT from the synapse. This is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including cocaine, dextromethorphan, tricyclic antidepressants, selective seratonin reuptake inhibitors (SSRIs) and seratonin norepinephrine reuptake inhibitors (SNRIs).
Serotonin is released into the space between neurons (synapse) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.
When humans smell food, dopamine is released to increase the appetite. The serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs that block 5-HT2C receptors make the body unable to recognize when it is no longer hungry or otherwise in need of nutrients, and are associated with increased weight gain, especially in people with a low number of receptors. ( Cymbalta and weight gain: https://www.ncbi.nlm...pubmed/25467076, https://www.ncbi.nlm...ubmed/24898363, https://www.ncbi.nlm...ubmed/21314871)
The expression of 5-HT2C receptors in the hippocampus follows a diurnal rhythm (24 hour cycles up and down) which is characterised by a peak at morning when the motivation to eat is strongest.

In humans, levels of 5-HT1A receptor activation in the brain show negative correlation with aggression, and a mutation in the gene that codes for the 5-HT2a receptor may double the risk of suicide for those with that genotype. Serotonin in the brain is not usually degraded after use, but is collected by serotonergic neurons by seratonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy.

In the digestive tract
The gut is surrounded by enterochromaffin cells, which release serotonin in response to food in the digestive system. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin.
If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5HT3 receptors in the chemoreceptors trigger zone that stimulate vomiting.

Bone metabolism
Alterations in serotonin levels and signaling have been shown to regulate bone mass. In humans, increased blood serotonin levels have been shown to be a significant negative predictor of low bone density. Serotonin can also be synthesized, at very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. Through 5-HT1b receptors, it negatively regulates bone mass, while it does so positively through 5-HT2b receptors and 5HT2c. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts (bone cells) culminating in FoxO1/ Creb and ATF4 dependent transcriptional events. These studies have opened a new area of research in bone metabolism that can be potentially harnessed to treat bone mass disorders. No research has been done on the effects of Cymbalta on bone mass.

[fishinghat]

Effects of Cymbalta on the Body (cont)

Organ development

Since serotonin signals resource availability it is not surprising that it affects organ development. Rodent experiment shows that neonatal exposure to SSRI's makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes, which are reversed by treatment with antidepressants.
Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2a and 5-HT2b, mediating liver compensatory regrowth. Serotonin present in the blood then stimulates cellular growth to repair liver damage. 5HT2B receptors also activate osteocytes, which build up bone. However, serotonin also inhibits osteoblasts, through 5-HT1B receptors. (Cymbalta and liver damage; https://www.ncbi.nlm...les/PMC3773985/
https://www.ncbi.nlm...les/PMC3182394/
https://www.ncbi.nlm...pubmed/22772703
https://www.ncbi.nlm...bmed/21694615).

Cardiovascular growth factor
Serotonin, in addition, causes endothelial (the inside lining of blood and lymphatic vessels) nitric oxide synthase activation. In blood, serotonin is collected from plasma by platelets, which store it. It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic (growth factor), to aid healing. (Cymbalta slows clotting; https://www.ncbi.nlm...pubmed/22054632
https://www.ncbi.nlm...bmed/18958440.)

Norepinephrine also called noradrenaline (NA), is an chemical that functions in the human brain and body as a hormone and neurotransmitter.The general function of norepinephrine is to mobilize the brain and body for action. Norepinephrine release is lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger, in the so-called fight-or-flight response. In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety. In the rest of the body, norepinephrine increases heart rate and blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, and inhibits voiding of the bladder and gastrointestinal motility. Norepinephrine can be converted by the body to epinephrine (adrenaline).
The sympathetic effects of norepinephrine include:
In the eyes, an increase in production of tears, making the eyes more moist., and pupil dilation through contraction of the iris dilator.

In the heart, an increase in the amount of blood pumped.

In brown adipose tissue, an increase in calories burned to generate body heat.

Multiple effects on the immune system. The sympathetic nervous system is the primary path of interaction between the immune system and the brain, and several components receive sympathetic inputs, including the thymus, spleen, and lymph nodes. However the effects are complex, with some immune processes activated while others are inhibited.

In the arteries, constriction of blood vessels, causing an increase in blood pressure.

In the kidneys, release of renin and retention of sodium in the bloodstream.

In the liver, an increase in production of glucose, either by glycogenolysis after a meal or by gluconeogenesis when food has not recently been consumed. Glucose is the body's main energy source in most conditions.

In the pancreas, increased release of glucagon, a hormone whose main effect is to increase the production of glucose by the liver.

In skeletal muscles, an increase in glucose uptake.

In adipose tissue (i. e., fat cells), an increase in lipolysis, that is, conversion of fat to substances that can be used directly as energy sources by muscles and other tissues.

In the stomach and intestines, a reduction in digestive activity. This results from a generally inhibitory effect of norepinephrine on the enteric nervous system, causing decreases in gastrointestinal mobility, blood flow, and secretion of digestive substances.

[fishinghat]

Effects of Cymbalta on the Body (cont)


In the central nervous system norepinephrine is released by the locus coeruleus and affects brain function in a number of ways. It enhances processing of sensory inputs, enhances attention, enhances formation and retrieval of both long term and working memory, and enhances the ability of the brain to respond to inputs by changing the activity pattern in the prefrontal cortex and other areas. The control of arousal level is strong enough that drug-induced suppression of the LC has a powerful sedating effect.

Research

Document #1
http://www.researchg...289a09b6b1a.pdf
Evaluation of Duloxetine as Micronuclei Inducer in an Acute and a Subchronic Assay in Mouse

micronucleated polychromatic erythrocytes (MNPEs) and micronucleated normochromatic erythrocytes (MNNEs)

In this assay, we found significant damage induced by duloxetine starting from the first time evaluated, showing the highest MNPE increase at the end of the assay. We observed a saturation effect as well, suggested by a decreasing relative efficiency with respect to each tested dose. In a second assay, we administered the antidepressant i.g. every day for 5 weeks (2, 6, and 12 mg/kg), and micronuclei analysis was performed at the end of each week. In this study, we also found a significant increase in both MNPEs and MNNEs which was clear by the second week of administration. Our results suggest that short-term as well as cumulative damage is produced by duloxetine. Thus, confirmation of the observed genotoxic potential in other models seems advisable, as well as caution when prescribing this antidepressant. Duloxetine, a potent serotonin and norepinephrine reuptake inhibitor which effectively desensitizes various autoreceptors and promotes neuroplasticity. The compound is used in stress urinary incontinence, and due to its analgesic efficacy it is also prescribed for chronic pain conditions such as diabetic peripheral neuropathy, fibromyalgia, chronic low back pain,and osteoarthritis knee pain.

Translation -
Cymbalta causes the development of damaged red blod cells which may or may not benormal in color and have a very small nucleus (the nucleus contains the cells DNA).
Also, Cymbalta improves neuroplasticity. The brain's ability to reorganize itself by forming new neural connections throughout life. Neuroplasticity allows the neurons (nerve cells) in the brain to compensate for injury and disease and to adjust their activities in response to new situations or to changes in their environment. Brain reorganization takes place by mechanisms such as "axonal sprouting" in which undamaged axons grow new nerve endings to reconnect neurons whose links were injured or severed. Undamaged axons can also sprout nerve endings and connect with other undamaged nerve cells, forming new neural pathways to accomplish a needed function.
Cymbalta downregulates the activity of the bladder control nerves.

Document #2
https://www.ncbi.nlm...pubmed/18973814
Neurobehavioral and genotoxic parameters of duloxetine in mice using the inhibitory avoidance task and comet assay as experimental models.
Duloxetine is a potent inhibitor of serotonin and noradrenaline reuptake, with weak effects on dopamine reuptakeDuloxetine did not induce genotoxic effects. Duloxetine did not produce any effect on memory after acute and subacute administration, suggesting that this antidepressant does not affect either memory acquisition or consolidation.

Translation - Cymbalta did not cause DNA damage.

Document #3
https://www.ncbi.nlm...les/PMC4713700/
Effects of duloxetine on microRNA expression profile in frontal lobe and hippocampus in a mouse model of depression
Our data showed that miRNA expression profile in frontal lobe and hippocampus was affected by duloxetine in mice model of depression. Duloxetine in particular has been reported to induce embryotoxicity in aquatic organisms.

Translation - RNA 'reads' the genes in the DNA and then produces the appropriate product. For example if a certain part of the DNA is for a digestive protein the RNA would actually copy that part of the DNA and then use that information to produce the desired protein. A microRNA ( miRNA) is a small RNA molecule that functions in stopping the RNA process and post-'copying' transcription mechanisms that are used by cells to increase or decrease the production of specific gene products (such as proteins or RNA). In simple terms Cymbalta regulates DNA product manufacturing in the frontal lobe and hippocampus.
The hippocampus is the part of the brain that is involved in memory forming, organizing, and storing. It is particularly important in forming new memories and connecting emotions and senses to memories. Because of this it is the center for memory based psychological learned responses (such as PTSD). It is also the center of the human fear circuits. The hippocampus receives input from neurotransmitter systems, including serotonin, norepinephrine, and dopamine systems. It also receives cholinergic input (responds to the neurotransmitter acetylcholine) from the medial septum, which regulates the hippocampal physiological state. The hippocampus is highly involved in sleep patterns including REM sleep. There is evidence that humans having experienced severe, long-lasting traumatic stress show atrophy (shrinking fur to lack of use) of the hippocampus more than of other parts of the brain.

Document #4
https://www.ncbi.nlm.../pubmed/9686935
Naunyn Schmiedebergs Arch Pharmacol. 1998 Jun;357(6):600-10.
Effect of long-term administration of duloxetine on the function of serotonin and noradrenaline terminals in the rat brain.
In rats treated for 21 days with duloxetine (20 mg/kg/day), the recovery times of dorsal hippocampus CA3 pyramidal neurons from microiontophoretic applications of 5-HT and NA were significantly increased, indicating ongoing reuptake blockade with the minipump in place delivering the drug. The remaining experiments were performed following a 48-h washout. Electrically evoked release of [3H]5-HT from preloaded slices was enhanced in the midbrain, presumably due to a desensitization of the somatodendritic 5-HT1D and 5-HT1A autoreceptors. In addition, evoked release of [3H]5-HT was increased in the hippocampus, which could have been due to the desensitization of the alpha2-adrenergic heteroreceptors located on the 5-HT terminals. In contrast, there was no change in the evoked release of [3H]5-HT in the frontal cortex despite decreased functioning of the 5-HT transporter found in this brain region. Similar to changes in 5-HT release, electrically evoked release of [3H]NA was enhanced in the hippocampus and frontal cortex of rats treated chronically with duloxetine. These increases in [3H]NA release were most likely due to the desensitization of the alpha2-adrenergic autoreceptor in the hippocampus and to the desensitization of the NA transporter in the frontal cortex, respectively. These data suggest that long-term administration of duloxetine is able to induce changes in the 5-HT and NA systems that lead to enhanced release of both 5-HT and NA in some limbic brain areas. Duloxetine, therefore, may be a useful antidepressant compound.
Translation - This research proves that Cymbalta affects the seratonin reuptake proteins. It also shows an increase in seratonin in the hippocampus and no change in seratonin in the frontal cortex. Other studies show that past the 2 month state seratonin levels drop with Cymbalta usage.

[fishinghat]

Effects of Cymbalta on the Body (cont)

Document #5
https://www.ncbi.nlm...les/PMC3362535/
Stress-Induced Changes of Hippocampal NMDA Receptors: Modulation by Duloxetine Treatment
It is now well established that the glutamatergic system contributes to the pathophysiology of depression. Exposure to stress, a major precipitating factor for depression, enhances glutamate release that can contribute to structural abnormalities observed in the brain of depressed subjects. We found that chronic stress increases the expression of the obligatory GluN1 subunit, as well as of the accessory subunits GluN2A and GluN2B at transcriptional and translational levels, particularly in the ventral hippocampus. Concomitant treatment with the antidepressant duloxetine was able to normalize the increase of glutamatergic receptor subunit expression, and correct the changes in receptor phosphorylation produced by stress exposure. Antidepressants may exert their activity in the long-term also via modulation of the glutamatergic synapse.
Translation - High glutamate (neurotransmitter) in the hippocampus contributes to depresssion. Cymbalta returns the glutamate gene function to normal activity in the hippocampus. Glutamate is an amino acid, one of the twenty amino acids used to construct proteins, and as a consequence is found in high concentration in every part of the body. In the nervous system it plays a special additional role as a neurotransmitter: a chemical that nerve cells use to send signals to other cells. In fact glutamate is by a wide margin the most abundant neurotransmitter in the vertebrate nervous system. It is used by every major excitatory information-transmitting pathway in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It is no wonder that Cymbalta can cause such varied side effects and withdrawal symptoms as it can potentially effect all nerve cells in the brain and nervous system.

Comment - Is it no wonder that Cymbalta has such a tremendous and varied effect on the human body while on the srug or during recovery/withdrawal afterward.

Document #6
J Biol Chem. 2014 Sep 5; 289(36): 25177–25185.
Synergistic Regulation of Glutamatergic Transmission by Serotonin and Norepinephrine Reuptake Inhibitors in Prefrontal Cortical Neurons*
We found that low dose SNRIs, by acting on 5-HT1A and α2-adrenergic receptors, synergistically reduced AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents and AMPAR surface expression in prefrontal cortex pyramidal neurons via a mechanism involving Rab5/dynamin-mediated endocytosis of AMPARs. Moreover, the depression of AMPAR-mediated excitatory postsynaptic currents by SNRIs required p38 kinase activity, which was increased by 5-HT1A and α2-adrenergic receptor co-activation in an activator of G protein signaling 3-dependent manner. These results have revealed a potential mechanism for the synergy between the serotonin and norepinephrine systems in the regulation of glutamatergic transmission in cortical neurons.
Translation - Cymbalta, by affecting both seratonin and alpha adrenaline receptors, affects glutamate receptor signaling in the prefrontal cortex of the brain.

Document #7
https://www.ncbi.nlm...pubmed/26135544
Antihyperalgesic effect of duloxetine and amitriptyline in rats after peripheral nerve injury: Influence of descending noradrenergic plasticity.

Noradrenaline (NA) and serotonin (5-HT) increase in the spinal cord by reuptake inhibition is considered to be main mechanism of the therapeutic effect of antidepressants in neuropathic pain. In vivo microdialysis in the lumbar spinal dorsal horn revealed that NA and 5-HT concentrations increased after intraperitoneal administration of duloxetine and amitriptyline (10 mg/kg, respectively). The present study suggests that NA/5-HT increase in the spinal cord is crucial in the antihyperalgesic effect of duloxetine and amitriptyline. The plastic change of the descending noradrenergic system does not obviously affect the analgesic efficacy of duloxetine and amitriptyline.

Translation -Cymbalta increases seratonin and noradrenaline levels in the spinal cord and reduces associated spinal pain.

Document #8
https://www.ncbi.nlm...pubmed/25154730
Eur J Pain. 2015 May;19(5):649-60. doi: 10.1002/ejp.586. Epub 2014 Aug 25.
A selective α2 B adrenoceptor agonist (A-1262543) and duloxetine modulate nociceptive neurones in the medial prefrontal cortex, but not in the spinal cord of neuropathic rats.

CONCLUSIONS: These data highlight that activation of the α2B adrenoceptor as well as inhibiting NA and 5-HT reuptake can result in modulating the ascending nociceptive system, in particular, dampening the firing of PR neurones in the mPFC.

Translation - Cymbalta does not effect the pain sensing nerves in the spinal cord but does reduce the activity of the nerves bringing signals back up to the prefrontal cortex and thus reducing the perception of pain.

Document #9
https://www.ncbi.nlm...les/PMC3171868/
Br J Pharmacol. 2011 Sep; 164(1): 159–169.
A spinal mechanism of action for duloxetine in a rat model of painful diabetic neuropathy
These results support the involvement of spinal 5-HT2A receptors in the ability of duloxetine to ameliorate painful diabetic neuropathy. Our data also suggest that the role of 5-HT2A receptors depends on the level of the neuraxis at which activation takes place, with peripheral activation contributing to tactile allodynia in diabetic rats, whereas spinal activation of this receptor alleviates tactile allodynia. The development of selective peripheral 5-HT2A receptor antagonists may offer a novel approach for the treatment of diabetic neuropathic pain.
Translation - Cymbalta seratonin receptor control helps control pain in peripheral (around the outside) nerves.

[fishinghat]

Effects of Cymbalta on the Body (cont)

Document #10
https://www.ncbi.nlm...pubmed/24933334
Pharmacol Biochem Behav. 2014 Sep;124:238-44. doi: 10.1016/j.pbb.2014.06.005. Epub 2014 Jun 14.
Augmentation of antidepressant effects of duloxetine and bupropion by caffeine in mice.
The objective of the present study was to evaluate the augmentation of antidepressant effects of duloxetine and/or bupropion with caffeine. Comparison between vehicle treated group and other groups showed significant decrease in immobility in all drug treated groups in both antidepressant models. Caffeine plus duloxetine treated group was better among the combination treated groups in terms of decrease in immobility and increase in norepinephrine, dopamine, and serotonin levels in hippocampi, cerebral cortices, and whole brain when compared to their respective monotherapy treated groups. These combination approaches may help in reducing the dose of duloxetine/bupropion, and consequently lower the associated side/adverse effects.
Translation - Caffiene in combination with Cymbalta helps decrease fatique and sluggishness (side effects of Cymbalta). It also increased concentrations of norepinephrine, dopamine and seratonin in the hippocampus, cerebral cortex and the whole brain.

Document #11
https://www.ncbi.nlm...pubmed/23522402
J Psychiatr Res. 2013 Jun;47(6):802-8. doi: 10.1016/j.jpsychires.2013.02.013. Epub 2013 Mar 19.
Chronic administration of duloxetine and mirtazapine downregulates proapoptotic proteins and upregulates neurotrophin gene expression in the hippocampus and cerebral cortex of mice.
In the present study, we examined the effects of two antidepressants, duloxetine and mirtazapine, on the expression of apoptotic (natural cell deatah) and neurotrophic proteins (promotes growth, survival and specialize) in the cerebral cortex and hippocampus of mice. Both duloxetine and mirtazapine produced antidepressant activity in the forced swimming test and induced increased cortical and hippocampal mRNA expression of BDNF. Duloxetine also increased Bcl-2, Bcl-xL, FGF-2, and NT-3 expression in the cerebral cortex, and FGF-2 expression in the hippocampus. Moreover, duloxetine reduced Bax and p53 expression in the hippocampus, and Bad expression in the cerebral cortex.
Translation - Cymbalta increased production of BDNF (brain-derived neurotrophic factor). BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses. In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking. It is also expressed in the retina, motor neurons, the kidneys, saliva, and the prostate. Cymbalta increases the production of one protein for apotosis (cell death), 2 for cell growth and survival and one cell membrane protein in the cerebral cortex. In addition it increases the protein for cell membranes in the hippocampus. Cymbalta decreases a protein antigen used to fight cellular tumors and 2 proteins used to promote cell death.

Document #12
https://www.ncbi.nlm...pubmed/23010381
Pharmacol Biochem Behav. 2012 Dec;103(2):408-17. doi: 10.1016/j.pbb.2012.09.011. Epub 2012 Sep 23.
The role of the NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of duloxetine in the forced swimming test.

Moreover, the administration of duloxetine (10mg/kg) produced a reduction in NOx levels in the hippocampus and cerebral cortex. Altogether the results suggest that the effect of duloxetine in the FST is dependent on either a blockade of NMDA receptors or an inhibition of NO.
Translation - Cymbalta reduces nitrous oxide levels in the hippocampua and cerebral cortex. Since it was first identified to play an important role in relaxation of blood vessels, nitric oxide has been demonstrated to regulate many biological processes, especially in the central nervous system. Of the three types of enzymes that produce nitric oxide in humans and rodents, neuronal type is found almost exclusively in the nervous system. This gaseous molecule is a nonclassical neurotransmitter, which maintains the activities of neural cells and regulates the normal functions of brain. It appears to play a role in promoting the transfer of nerve signals from one neuron to another, maintaining the synaptic strength. Meanwhile, nitric oxide is a unique regulator on neurogenesis (new nerve cell production) and synaptogenesis, producing the positive or negative effects upon different signal pathways or cellular origins and locations. Based on its significant roles in neural plasticity, nitric oxide is involved in a number of central nervous diseases, such as ischemia, depression, anxiety, and Alzheimer's disease.

Document #13
https://www.ncbi.nlm...pubmed/21820879
Psychiatry Res. 2011 Nov 30;194(2):157-62. doi: 10.1016/j.pscychresns.2011.03.011. Epub 2011 Aug 6.
Duloxetine's modest short-term influences in subcortical structures of first episode drug-naïve patients with major depressive disorder and panic disorder.
The patients had consistent changes of volumes in bilateral nucleus accumbens, left putamen, left hippocampus and brainstem after 6 weeks of treatment with duloxetine. There were no consistent changes in other subcortical structures. There were modest increases of the volumes of the above areas, which were not significant after false discovery correction by FIRST F-test comparisons. The volumetric increases were correlated with responses of clinical symptoms. The results suggested that duloxetine possibly contributed to modest increases in several subcortical areas of these patients with remission.
Translation - Consistent changes of volumes in bilateral nucleus accumbens, a region of the forebrain, (As a whole, the nucleus accumbens has a significant role in the cognitive processing of aversion, motivation, pleasure, reward and reinforcement learning; hence, it has a significant role in addiction. It plays a lesser role in processing fear (a form of aversion), impulsivity, and the placebo effect. It is involved in the encoding of new motor programs as well.), left putamen (located at the base of the forebrain it's main function is to regulate movements and influence various types of learning. It employs GABA, acetylcholine, and enkephalin to perform its functions. The putamen also plays a role in degenerative neurological disorders, such as Parkinson's disease.), left hippocampus and brainstem after 6 weeks of treatment with duloxetine.

Document #14
https://www.ncbi.nlm...pubmed/20381469
Brain Res. 2010 Jun 23;1341:93-9. doi: 10.1016/j.brainres.2010.03.086. Epub 2010 Apr 8.
Comparison of neurogenic effects of fluoxetine, duloxetine and running in mice.
Both running and fluoxetine, but not duloxetine, increased the percentage of new cells that became neurons. In the open-field test, animals treated with either drug spent less time in the center than controls and runners. In addition, fluoxetine treatment resulted in reduced locomotor activity. Together, these data show that the neurogenic response to exercise is much stronger than to antidepressants and imply a low likelihood that anxiolytic effects of these drugs are mediated by adult neurogenesis in C57Bl/6 mice.

Document #15
https://www.ncbi.nlm...pubmed/20159945
Mol Pharmacol. 2010 May;77(5):846-53. doi: 10.1124/mol.109.063081. Epub 2010 Feb 16.
Long-Term duloxetine treatment normalizes altered brain-derived neurotrophic factor expression in serotonin transporter knockout rats through the modulation of specific neurotrophin isoforms.
We demonstrate that chronic treatment with the antidepressant duloxetine (DLX) was able to normalize the expression of BDNF mRNA-coding exon (IX) in the hippocampus and prefrontal cortex of SERT KO rats through the modulation of selected neurotrophin transcripts, whose expression was up-regulated by DLX only in SERT KO rats. On the other hand, the modulation of BDNF protein by DLX in frontal cortex was abolished in mutant rats. These data suggest that animals with a genetic defect of the serotonin transporter maintain the ability to show neuroplastic changes in response to antidepressant drugs. Because these animals show depression-like behavior, the region and isoform-specific increase of BDNF levels may be a mechanism activated by long-term antidepressant treatment to restore normal plasticity that is defective under genetic dysfunction of the serotonin transporter.
Translation - Cymbalta returns BDNF to proper levels and a return of neural plasticity (the ability of the brain to change and develop through it's life).

[fishinghat]

Effects of Cymbalta on the Body (cont)

Document #16
https://www.ncbi.nlm...pubmed/18751896
Neurochem Res. 2009 Mar;34(3):542-55. doi: 10.1007/s11064-008-9818-2. Epub 2008 Aug 27.
Brain region-specific effects of short-term treatment with duloxetine, venlafaxine, milnacipran and sertraline on monoamine metabolism in rats.
Serotonin noradrenaline reuptake inhibitors (SNRIs; duloxetine, venlafaxine, milnacipran) and a serotonin-selective reuptake inhibitor (SSRI; sertraline) elevated serotonin (5-HT) levels in the midbrain (MB). Duloxetine and venlafaxine increased 5-HT levels in the brainstem and 5-HT terminal areas, whereas milnacipran and sertraline increased levels in the brainstem only. Significant reductions in 5-HT turnover were observed in various forebrain regions, including the hippocampus and hypothalamus, after treatment with all of the tested drugs except for milnacipran. In addition, there was reduced 5-HT turnover in the dorsolateral frontal cortex (dlFC), the medial prefrontal cortex (mPFC), and both the dlFC and the mPFC after treatment with duloxetine, sertraline, and venlafaxine, respectively. Venlafaxine significantly increased dopamine (DA) levels in the nucleus accumbens (NAc) and the substantia nigra and decreased DA turnover in the NAc. Similar changes were observed after treatment with duloxetine and sertraline in the NAc, whereas milnacipran increased DA levels in the mPFC. Limited increases in noradrenaline levels were detected after treatment with duloxetine, venlafaxine, or sertraline, but not after treatment with milnacipran. These results show that SNRIs and SSRIs induced region-specific monoaminergic changes after short-term treatment.
Translation - Cymbalta initially increased seratonin in the brain stem, reduced reuptake (reuse) in the hippocampus, hypothalmus and frontal cortex. Also, Cymbalta icreased dopamine levels and decreased reuptake of dopamine in the nucleus accumbens and the substantia nigra(plays an important role in reward and movement). It also caused small increases in noradrenaline.

Document #17
https://www.ncbi.nlm...pubmed/17327885
Neuropsychopharmacology. 2007 Nov;32(11):2351-9. Epub 2007 Feb 28.
Chronic duloxetine treatment induces specific changes in the expression of BDNF transcripts and in the subcellular localization of the neurotrophin protein.
There is growing evidence that brain-derived neurotrophic factor (BDNF) can be relevant to mood disorders and that modulation of its biosynthesis following prolonged antidepressant treatment may contribute to neuroplastic changes required for clinical response. In the present study, we investigated the effects of the novel antidepressant duloxetine on BDNF in the rat brain. Duloxetine is a serotonin-norepinephrine reuptake inhibitor that differs from other antidepressants by virtue of its balanced potency on both neurotransmitter systems. We found that chronic, but not acute, treatment with duloxetine produces a robust increase of exon V BDNF mRNA levels in frontal cortex when the animals were killed 1 or 24 h after the last administration. The expression of the neurotrophin was also increased in other cortical subregions, but not in the hippocampus. We also found that the increased expression of BDNF in frontal cortex was mainly sustained by enhanced mRNA levels for exons I and III, whereas the expression of exon IV was reduced. Protein analysis in different subcellular fractions showed that chronic treatment with duloxetine, but not with the prototypical SSRI fluoxetine, reduced mature BDNF in the cytosol, but markedly increased its levels in the crude synaptosomal fraction. Our data suggest that chronic treatment with the novel antidepressant duloxetine not only produces a marked upregulation of BDNF mRNA and protein, but may also affect the subcellular redistribution of the neurotrophin. These changes might improve synaptic plasticity and cognitive function that are defective in depressed subjects.
Translation - Chronic treatment with Cymbalta not only produces a marked increase in the function of the BDNF mRNA but also the manufacturing of BDNF itself, and may also affect the subcellular redistribution of BDNF).

Document #18
https://www.ncbi.nlm.../pubmed/9686935
Effect of long-term administration of duloxetine on the function of serotonin and noradrenaline terminals in the rat brain.
Abstract
Duloxetine, an inhibitor of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake processes, has been developed as a potential antidepressant drug. //In rats treated for 21 days with duloxetine (20 mg/kg/day), the recovery times of dorsal hippocampus CA3 pyramidal neurons from microiontophoretic applications of 5-HT and NA were significantly increased, indicating ongoing reuptake blockade with the minipump in place delivering the drug. The remaining experiments were performed following a 48-h washout. Electrically evoked release of [3H]5-HT from preloaded slices was enhanced in the midbrain, presumably due to a desensitization of the somatodendritic 5-HT1D and 5-HT1A autoreceptors. In addition, evoked release of [3H]5-HT was increased in the hippocampus, which could have been due to the desensitization of the alpha2-adrenergic heteroreceptors located on the 5-HT terminals. In contrast, there was no change in the evoked release of [3H]5-HT in the frontal cortex despite decreased functioning of the 5-HT transporter found in this brain region. Similar to changes in 5-HT release, electrically evoked release of [3H]NA was enhanced in the hippocampus and frontal cortex of rats treated chronically with duloxetine. These increases in [3H]NA release were most likely due to the desensitization of the alpha2-adrenergic autoreceptor in the hippocampus and to the desensitization of the NA transporter in the frontal cortex, respectively. These data suggest that long-term administration of duloxetine is able to induce changes in the 5-HT and NA systems that lead to enhanced release of both 5-HT and NA in some limbic brain areas. Duloxetine, therefore, may be a useful antidepressant compound.
Translation - Demonstrated the blocking of seratonin reuptake by Cymbalta. It also increased seratonin levels in the hippocampus. Although seratonin reuptake was blocked in the frontal cortex seratonin levels remained constant. Chronic use (21 days is chronic?) showed increase release of noradrenaline in the hippocampus and frontal cortex.

Document #19
https://www.ncbi.nlm.../pubmed/9580577
J Pharmacol Exp Ther. 1998 May;285(2):404-12.
Electrophysiological characterization of the effect of long-term duloxetine administration on the rat serotonergic and noradrenergic systems.
The firing rate of DRN neurons was decreased after 2 days of duloxetine, but returned to the control level after 21-day administration. This recovery of firing rate was presumably due to the desensitization of the DRN somatodendritic 5-HT1A autoreceptors found after long-term duloxetine administration. Overall serotonergic tone was assessed by examining the ability of the 5-HT1A antagonist WAY 100635 to alter hippocampal firing. WAY 100635 increased hippocampal firing rates in 21-day treated rats to a greater extent than in 2-day treated or control rats, suggesting that long-term administration induced an increase in endogenous levels of 5-HT in postsynaptic regions. This increase in 5-HT levels was accompanied by selective changes in the 5-HT and NE systems induced by long-term duloxetine administration, i.e., the desensitization of the alpha-2 adrenergic heteroreceptor on 5-HT terminals and the continued blockade of the 5-HT transporters. In contrast, the sensitivity of the alpha-2 adrenergic and terminal 5-HT1B autoreceptors, as well as that of the postsynaptic 5-HT1A receptor after 21-day treatment was unchanged. Therefore, this study demonstrates that duloxetine increases serotonergic tone in a limbic forebrain structure and may therefore be effective in the treatment of depression.
Translation - Cymbalta initially increased the firing of nerve cells in the dorsal raphe nucleus (The dorsal raphe nucleus is located on the midline of the brainstem The dorsal raphe nucleus have long been implicated in depression. Some studies have suggested that the dorsal raphe may be decreased in size in people with depression and, paradoxically, an increased cell density in those who commit suicide.) but firing rates returned to normal after 21 days due to fatique in the seratonin receptors. It also increased seratonin in the forebrain.

Document #20
https://www.ncbi.nlm.../pubmed/9105878
Eur J Pharmacol. 1997 Mar 26;323(1):69-73.
Electrophysiological effects of fluoxetine and duloxetine in the dorsal raphe nucleus and hippocampus.
The cellular electrophysiological effects of duloxetine (LY248686), a dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake inhibitor, and the selective serotonin reuptake inhibitor fluoxetine were compared on spontaneously active neurons in the dorsal raphe nucleus and the hippocampus of chloral hydrate-anesthetized male rat. Systemic intravenous administration of duloxetine or fluoxetine inhibited dorsal raphe nucleus cell firing in a dose-dependent manner; duloxetine suppressed cell firing at significantly lower doses (ED100 1.4 +/- 0.3 mg/kg) than fluoxetine (ED100 10.0 +/- 2.0 mg/kg). In the hippocampus, microiontophoretic application of duloxetine or fluoxetine (0.01 M, pH 5.5; 5-40 nA) produced minimal inhibition of cell firing.
Translation - Cymbalta inhibited dorsal raphe nucleus cell firing. In the hippocampus little decrease was noted in cell firing.

[fishinghat]

Effects of Cymbalta on the Body (cont)

Document #21
https://www.ncbi.nlm.../pubmed/8613930
J Pharmacol Exp Ther. 1996 Apr;277(1):278-86.
Blockade of the serotonin and norepinephrine uptake processes by duloxetine: in vitro and in vivo studies in the rat brain.
In in vitro uptake experiments, duloxetine inhibited [3H]5-hydroxytryptamine (5-HT) and [3H]norepinephrine (NE) uptake in hippocampus slices of control rats with IC50 values of 28 and 46 nM, respectively. The uptake of both[3H]5-HT and [3H]NE was equipotently inhibited in hippocampus slices prepared from rats treated for 2 days with different doses of duloxetine (5, 10, 15 and 20 mg/kg/day s.c.). In in vivo electrophysiological experiments in the hippocampus, the effects of duloxetine on the suppression of CA3 pyramidal neuronal firing activity by microiontophoretically applied 5-HT and NE were examined with two modes of administration. Five successive i.v. injections (2 mg/kg each) significantly and dose-dependently prolonged the recovery time of the firing activity of hippocampus CA3 pyramidal neurons from the 5-HT applications. A 2-day treatment (10, 15 and 20 mg/kg/day s.c.) also increased the recovery time in a dose-dependent manner. Whereas the recovery time from NE applications was unaffected by low doses of duloxetine (2 mg/kg i.v.; 10 mg/kg/day for 2 days), it was prolonged significantly by higher doses (8 and 1 0 mg/kg iv.; 20 mg/kg/day for 2 days). Acute i.v. injections of duloxetine suppressed the spontaneous firing activity of dorsal raphe 5-HT and locus ceruleus NE neurons with ED50 values of 99 and 475 microgram/kg, respectively. Taken together, the present results confirmed that duloxetine is a dual 5-HT/NE uptake inhibitor. Furthermore, the results obtained in in vivo experiments indicate that duloxetine has a preferential inhibitory effect on the 5-HT transporter.
Translation - Cymbalta inhibited the reuptake of both seratonin and noradrenaline in the hippocampus. It inhibited seratonin reuptake more than noradrenaline.

Document #22
https://www.ncbi.nlm...les/PMC3413810/
J Mol Neurosci. 2012 Sep; 48(1): 167–175.
Differential BDNF Responses of Triple Versus Dual Reuptake Inhibition in Neuronal and Astrocytoma Cells as well as in Rat Hippocampus and Prefrontal Cortex
,1,2,3 Gunter Kenis,1,2 Maria S. Quinton,3 Sharon Engel,3 Larry Melnick,3 and Rudy Schreiber3,4
Abstract
Twenty-one days of oral treatment (30 mg/kg) with the dual serotonin/noradrenaline reuptake inhibitor duloxetine or the triple serotonin/noradrenaline/dopamine reuptake inhibitor DOV 216,303 restored BDNF protein levels in the rat hippocampus, which were initially decreased due to injection stress. Increased BDNF levels support the neurotrophic hypothesis of depression, but our findings do not clearly evidence that the BDNF response after triple reuptake inhibitors is more effective than after dual reuptake inhibitors. Moreover, the data suggest that the role of BDNF in neurons and astrocytes is complex and likely depends on factors including specificity of cell types in different brain regions, cell–cell interactions, and different mechanisms of action of antidepressants used.
Translation - Cymbalta returned BDNF levels to normal in the hippocampus within 21 days.

Document #23
https://www.ncbi.nlm...les/PMC3176563/
Neuropsychopharmacology. 2011 Oct; 36(11): 2266–2275.
Short-Term Duloxetine Administration Affects Neural Correlates of Mood-Congruent Memory
Using a double-blind, placebo-controlled, cross-over design, we investigated the effect of a short-term treatment (14 days) with the dual reuptake inhibitor duloxetine on neural correlates of mood-congruent and mood-incongruent memory formation and retrieval in healthy volunteers who underwent a sad mood induction procedure. Duloxetine did not affect acute mood state or memory performance, but interacted with brain processes mediating mood-congruent memory. It decreased activity related to successful memory formation for mood-congruent and -incongruent items in a set of brain regions comprising the putamen and the middle frontal gyrus, as well as the middle and the anterior cingulate cortex. Duloxetine specifically increased amygdala activity related to successful memory retrieval for mood-incongruent items. Here we show that short-term administration of duloxetine affects the neural correlates of emotional memory formation and retrieval in a set of brain regions whose processing is related to affective state and its regulation. While duloxetine suppressed the neural correlates of emotional memory formation in general, it specifically enhanced amygdala processes associated with mood-incongruent memory retrieval. This pattern of results shows how an antidepressant may reduce emotional memory formation and reverse mood-congruent processing biases at retrieval.
Translation - A 14 day treatment with Cymbalta decreased activities related to memory formation in the putamen, frontal gyrus and anterior cingulate cortex. On the other hand it increased memory retrieval in the amygdala.

Document #24
https://www.ncbi.nlm...les/PMC4713700/
Int J Clin Exp Pathol. 2015; 8(11): 15454–15461.
Effects of duloxetine on microRNA expression profile in frontal lobe and hippocampus in a mouse model of depression
A significant upregulation of miR-132 and miR-18a in hippocampus in the duloxetine treatment group compared with model group, whereas the levels of miR-134 and miR-124a were significantly downregulated. Furthermore, miR-18a showed significant upregulation in frontal lobe in the duloxetine treatment group relative to model group. Our data showed that miRNA expression profile in frontal lobe and hippocampus was affected by duloxetine in mice model of depression. The effect was especially pronounced in the hippocampus, suggesting that hippocampus might be the action site of duloxetine, which presumably worked by regulating the expression of miRNA levels.
Translation- Cymbalta increased the activity of two miRNA in the hippocampus (miRNA-132 which functions to regulate the expression levels of other genes) by several mechanisms, generally reducing protein levels through the cleavage of mRNAs or the repression of their translation. Several targets for miR-132 have been described, including mediators of neurological development, synaptic transmission, inflammation and angiogenesis.; and miR-18a which triggers the function of other RNA) and decreases the function of two other miRNA (miR-134 is a brain-specific microRNA localised in hippocampal neurons and indirectly regulate synaptic development and is thought to mediate Creb protein giving it a role in higher brain functions such a memory formation; and miR-124a which has been found to be the most abundant microRNA expressed in nerve cells. It can change the structure of Glutamate receptors in the prefrontal cortex.)

Document #25
https://www.ncbi.nlm...les/PMC3055320/
Neuropsychopharmacology. 2010 Oct; 35(11): 2305–2317.
Effects of Duloxetine Treatment on Brain Response to Painful Stimulation in Major Depressive Disorder
Treatment with duloxetine was associated with a significant reduction in brain responses to painful stimulation in MDD patients in regions generally showing abnormally enhanced activation at baseline. Clinical improvement was associated with pain-related activation reductions in the pregenual anterior cingulate cortex, right prefrontal cortex, and pons. Pontine changes were specifically related to clinical remission. Increased baseline activations in the right prefrontal cortex and reduced deactivations in the subgenual anterior cingulate cortex predicted treatment responders at week 8. This is the first fMRI study addressed to assess the effect of duloxetine in MDD. As a novel approach, the application of painful stimulation as a basic neural stressor proved to be effective in mapping brain response changes associated with antidepressant treatment and brain correlates of symptom improvement in regions of special relevance to MDD pathophysiology.
Translation - Cymbalta reduced pain nerve signals in the pregenual anterior cingulate cortex (It plays a role in a wide variety of autonomic functions, such as regulating blood pressure and heart rate and is involved in certain higher-level functions, such as reward anticipation, decision-making, impulse control, and emotion.), right prefrontal cortex, and pons (The pons is part of the brainstem that conduct signals from the brain down to the cerebellum and medulla, and tracts that carry the sensory signals up into the thalamus.The pons contains nuclei that relay signals from the forebrain to the cerebellum, along with nuclei that deal primarily with sleep, respiration, swallowing, bladder control, hearing, equilibrium, taste, eye movement, facial expressions, facial sensation, and posture.).

[fishinghat]

Effects of Cymbalta on the Body (cont)

Document #26
https://www.ncbi.nlm...pubmed/25880400
2015 Apr 14;15:82. doi: 10.1186/s12888-015-0457-2.
Multimodal functional and structural neuroimaging investigation of major depressive disorder following treatment with duloxetine.
Participants were medication-free MDD patients (n = 32; mean age 40.2 years) in an acute depressive episode and healthy controls matched for age, gender, and IQ (n = 25; mean age 38.8 years). MDD patients received treatment with duloxetine 60 mg daily for 12 weeks with an optional dose increase to 120 mg daily after 8 weeks. All participants had serial imaging at weeks 0, 1, 8, and 12 on a 3 Tesla magnetic resonance imaging (MRI) scanner. Neuroimaging tasks included emotional facial processing, negative attentional bias (emotional Stroop), resting state functional MRI and structural MRI.
RESULTS: In the emotional Stroop task, increased posterior cingulate activation in MDD patients normalized following treatment. An early increase in hippocampal volume was predictive of clinical response.
Translation - Cymbalta normalized activation of the posterior cingulate. Imaging studies indicate a prominent role for the posterior cingulate cortex in pain and episodic memory retrieval. Increased size of posterior ventral cingulate cortex is related to working memory decline. The posterior cingulate cortex has been implicated as a key part of several control networks. The posterior cingulate cortex has also been firmly linked to prominent emotional experiences . Thus, it has been hypothesized that the emotional importance of personal memories may contribute to the strength and consistency of activity in the posterior cingulate cortex upon successful recollection of these memories. The posterior cingulate cortex is significantly activated by emotional stimuli.

Document #27
https://www.ncbi.nlm...pubmed/21195195
Neuroimage. 2011 Mar 15;55(2):825-31. doi: 10.1016/j.neuroimage.2010.12.051. Epub 2010 Dec 30.
Subchronic duloxetine administration alters the extended amygdala circuitry in healthy individuals.
We used functional magnetic resonance imaging in nineteen healthy volunteers to assess the effect of two weeks of administration of the combined serotonin and norepinephrine reuptake inhibitor duloxetine (60 mg) on reactivity and functional connectivity within the affective neurocircuitry in a double-blind, placebo-controlled, crossover design. Using an emotional face matching task we demonstrated that duloxetine reduced neural responses in affect processing regions including the amygdala, the anterior insula, the thalamus and the ventral aspect of the anterior cingulate cortex. Additionally, functional coupling between the amygdala and the anterior insula was enhanced by the drug. These results suggest that duloxetine attenuates the bottom-up processing of biologically salient information in an extended amygdala circuitry, while at the same time possibly potentiating the effective communication between its subparts. Since hyperactivation of the same affective neurocircuitry is thought to underlie emotional dysfunction in depression, these results suggest a putative neural mechanism through which duloxetine could normalize typical negativity biases in depression.
Translation - Cymbalta reduced nerve responses in the amygdala, anterior insula (The insulae are believed to be involved in consciousness and play a role in diverse functions usually linked to emotion or the regulation of the body's homeostasis. These functions include perception, motor control, self-awareness, cognitive functioning, and interpersonal experience. In relation to these, it is involved in psychopathology.), thalmus (Some of its functions are the relaying of sensory and motor signals to the cerebral cortex, and the regulation of consciousness, sleep, and alertness.) and cingulate cortex. Communication between the amygdala and the anterior insula were increased.

Document #28
https://www.ncbi.nlm...pubmed/23507186
Psychoneuroendocrinology. 2013 Sep;38(9):1824-8. doi: 10.1016/j.psyneuen.2013.02.009. Epub 2013 Mar 16.
NGF serum levels variations in major depressed patients receiving duloxetine.
METHODS: 30 MDD patients and 32 healthy controls were assessed using Hamilton depression scale (HAM-D) and monitored for NGF serum levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively.
RESULTS: According to early clinical response to duloxetine (defined at week 6 by reduction >50% of baseline HAM-D score), MDD patients were distinguished in early responders (ER) and early non-responders (ENR), who overall reached clinical response at week 12. Laboratory analysis showed overall significant lower baseline NGF levels among depressed patients compared to healthy controls, not significantly in ER and significantly in ENR. During duloxetine treatment NGF levels further decreased in association with clinical response, reaching significantly lower values in ER at W6 compared to controls, and in ENR at W12 compared to baseline.

CONCLUSIONS: A decrease in NGF levels during duloxetine treatment in association to clinical response could be indicative of a relative restoring of NEI stress-adaptation system.
Translation - Nerve growth factor concentrations were lower in depressed patients. Cymbalta further lowered nerve growth factor concentrations.

Document #29
https://www.ncbi.nlm...pubmed/20305306
Neuropsychopharmacol Hung. 2010 Mar;12(1):301-7.
[The effects of duloxetine on beta-actin stress response in rat brain].
Abstract
Depression is a frequent prodromal symptom of Alzheimer's disease (AD). Stress factors play an important role in the etiopathology of both diseases, since increased corticosteroid levels caused by chronic stress indirectly induce neuronal damage. The aim of our experiments was to evaluate the changes induced by stress in the transcription of amyloid precursor protein (APP), mitogen activated protein kinase-1 (MAPK-1) and beta-actin, of which the latest plays a leading role in synaptic plasticity. Additionally we intended to examine how duloxetine - a serotonin-norepinephrin reuptake inhibitor type antidepressant - would modify the stress-induced changes. Wistar rats were exposed to immobilization stress for five hours daily through 21 days, while part of the animals received 45 mg/bwkg of duloxetine. At the end of the third week total RNA was purified from the cortex and hippocampus. The amount of beta-actin, APP and MAPK-1 mRNA was determined by real time PCR method. On protein level, semiquantitative measurement was performed by Western blot. The expression of beta-actin mRNA in the animals exposed to stress was four times as intense as in the control group. The increase in the beta-actin mRNA levels was repressed by the duloxetine treatment. In the case of APP and MAPK-1 no changes were detected.
Translation- Stress increases activity of the beta-actin mRNA (major part of muscle contractions) and Cymbalta decreased the activity of the beta-actin mRNA

[fishinghat]

Effects of Cymbalta on the Body (cont)

Document #30
https://www.ncbi.nlm...pubmed/19020498
Neuropsychopharmacology. 2009 May;34(6):1523-32. doi: 10.1038/npp.2008.208. Epub 2008 Nov 19.
Acute stress responsiveness of the neurotrophin BDNF in the rat hippocampus is modulated by chronic treatment with the antidepressant duloxetine.
Adult male Sprague-Dawley rats were treated for 21 days with vehicle or with the SNRI duloxetine and, 24 h after the last injection, exposed to an acute swim stress (5 min) before being killed 15 min later. We found that chronic duloxetine treatment was able to modulate the rapid transcriptional changes of BDNF isoforms produced by an acute swim stress. Indeed whereas the mRNA levels of BDNF exon IV were upregulated by stress in vehicle as well as in duloxetine-treated rats, a significant increase of exon VI and exon IX was only found in rats that were pretreated with the antidepressant. These differential effects are in part because of selective changes in signaling pathways involved in the control of BDNF transcription. Moreover, the acute stressful episode significantly increased the levels of mature BDNF protein in the synaptosomal compartment in rats that were pretreated with the antidepressant, but not in control animals. Our results suggest that chronic antidepressant treatment might affect the responsiveness of BDNF under stressful conditions, suggesting that pharmacological intervention could 'prime' neuroprotective pathways and render them more responsive to preserve cell function and viability.
Translation - Stress increases BDNF concentration but Cymbalta treatment decreased the concentration. Pretreatment with Cymbalta had the opposite effect.

Document #31
https://www.ncbi.nlm...pubmed/18704370
Psychopharmacology (Berl). 2008 Dec;201(2):285-92. doi: 10.1007/s00213-008-1276-7. Epub 2008 Aug 14.
Basal and stress-induced modulation of activity-regulated cytoskeletal associated protein (Arc) in the rat brain following duloxetine treatment.
RESULTS: Although a limited increase of Arc messenger RNA (mRNA) levels was found in some structures after acute antidepressant administration, a marked up-regulation of its gene expression was found after chronic treatment, primarily at the level of frontal cortex. The changes observed after prolonged duloxetine administration strongly correlates with those previously reported on brain-derived neurotrophic factor mRNA levels Calabrese et al. In addition, we found an anatomical-specific influence of chronic duloxetine on stress-dependent Arc modulation, which was limited to the frontal cortex.
CONCLUSIONS: We suggest that these neuroadaptive changes, among others, might contribute to the normalization of neuroplastic defects associated with mood disorders.
Translation - Chronic use of Cymbalta increases Arc concentrations in the frontal cortex. Arc is widely considered to be an important protein in neurobiology because of its activity regulation, localization, and utility as a marker for plastic changes in the brain. Dysfunctions in the production of Arc protein has been implicated as an important factor in understanding of various neurological conditions including: Amnesia; Alzheimer's disease; Autism spectrum disorders; and, Fragile X syndrome.

[fishinghat]

Effects of Cymbalta on the Body (cont)

Misc.
http://www.ncbi.nlm....pubmed/23732229
With these findings, we propose a model by which acute SSRI administration, by altering neural activity in the extended amygdala and hippocampus, enhances both acquisition and expression of cued fear conditioning, but impairs the expression of contextual fear conditioning

http://www.ncbi.nlm....pubmed/23675317
We evaluated the effect of four weeks of 0.7 mg/kg fluoxetine on long-term potentiation (LTP) and long-term depression (LTD) in the CA1 hippocampal subfield. Recordings in hippocampal slices revealed profound deficits in LTP and LTD at Schaffer collateral-CA1 synapses associated to increased spine density and enhanced presence of mushroom-type spines, as revealed by Golgi staining

https://www.ncbi.nlm...pubmed/23400819
Overall, the results suggest that citalopram at the recommended human doses induces some genetic alterations, which can adversely affect the normal cellular functioning in mice. The mechanism(s) by which citalopram cause this adverse effect appear related, in part, to primary DNA strand breakage as detected by the comet assay as well as clastogenic and aneugenic events as detected by the FISH assay. Therefore, the clinical use of citalopram must be weighed against the risks of genetic damages in citalopram users.

https://www.ncbi.nlm...pubmed/23280034
The results showed that the drug fluoxetine was SCE and sperm abnormalities inducer. The response of this compound was dose-dependent, and showed that the highest tested dose increased about two times SCE and four times the sperm abnormalities control level. The cellular proliferation kinetics was not affected by the chemical, and the mitotic indexes were slightly diminished with the highest dose. The percentage of sperm count and sperm motility decreased (p < 0.01) with increased the dose of treatment.

https://www.ncbi.nlm...pubmed/23232079
Overall, this study provides that citalopram at the recommended human doses after long-term treatment is genotoxic for mouse germ cells (DNA breaks). Thus, male patients receiving citalopram may stand at higher risk for abnormal reproductive outcomes, particularly in the reproductive ages.

https://www.ncbi.nlm...pubmed/22750076
Genetic changes occurring in somatic cells of the wing's imaginal discs, cause the formation of mutant clones on the wing blade. The results of this study show that citalopram had a genotoxic effect in the Drosophila SMART. Sertraline, however, did not show any genotoxic effect in balancer heterozygous wings. This study concluded that more information is needed to be certain regarding the mutagenic effects of sertraline.

https://www.ncbi.nlm...pubmed/21937534
Olanzapine (OLZ), risperidone (RPD) and quetiapine (QTP) are atypical antipsychotic drugs and are commonly used for the treatments of schizophrenia and bipolar disorders.However, the application of the highest drug concentrations (250 mg/L and above) caused the sterility in lymphocyte cultures. It is concluded that the tested three different atypical antipsychotic drugs can be used safely, but it is necessary to consider the cytotoxic effects that are likely to appear depending on the doses exposed.

https://www.ncbi.nlm...pubmed/20542924
Our results indicated that the tested antipsychotic drug did not induce SCEs in lymphocytes of treated cultures. However, the application of the highest OLZ concentration caused oxidative stress. It is concluded that the OLZ can be used safely, but it is necessary to consider the tissue damages that are likely to appear depending on the oxidative stress.

https://www.ncbi.nlm...pubmed/18804223
Patients treated with selective serotonin reuptake inhibitors had a mean of 8.1% +/- 5.4% normal forms per ejaculate. A significant increase in the amount of denatured single strand DNA in total cellular DNA was found in patients treated with selective serotonin reuptake inhibitors compared with that in controls (43.2% +/- 11.4% vs 21.4% +/- 10.6%, p = 0.01). Each semen analysis parameter significantly correlated with treatment duration.

https://www.ncbi.nlm...pubmed/12904104
Classical antidepressants such as monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressants (TCAs) seem to have the highest potential to induce liver damage compared with the newer drugs such as selective serotonin re-uptake inhibitors (SSRIs). The potential for severe hepatotoxicity associated with nefazodone is stressed. Guidelines for therapy and prevention of antidepressant-induced hepatotoxicity are also discussed.

https://www.ncbi.nlm...pubmed/11482523
The effects of acute (24 h) exposure to the antidepressants amitriptyline, imipramine (both tricyclics), fluoxetine (a selective serotonin re-uptake inhibitor) and tranylcypromine (a monoamine oxidase inhibitor) on DNA damage in cultured C6 rat glioma cells were determined using an alkaline comet assay. The data show that the antidepressants induce significant amounts DNA damage in C6 cells

https://www.ncbi.nlm...pubmed/20851831
The recombinogenic potential of this antidepressant in A. nidulans may be associated with the recombinational repair of citalopram-induced DNA strand breaks

https://www.ncbi.nlm...pubmed/15036127
Patients with both generalized anxiety disorder and major depression exposed to daily doses of sertraline do not indicate a possible clastogenic hazard.

https://www.ncbi.nlm...les/PMC3702119/
We conclude that although, Wellbutrin exerts potential genotoxic effects in cultured lymphocytes, its cytogenetic effects are very unlikely to occur in blood cultures of WB-administered subjects.

https://www.ncbi.nlm...pubmed/16751836
Neurotoxic reaction to citalopram.

Summary

Cymbalta can
⦁ cause weight gain
⦁ cause liver damage
⦁ slow clotting
⦁ damage red blood cells beginning in 2 weeks and is cumulative
⦁ does not damage DNA
⦁ control/alter RNA and miRNA performamce resulting in different effects than the DNA genes are coded for
⦁ alter BDNF mRNA but also the manufacturing of BDNF (brain-derived neurotrophic factor) itself. Thus RNA and BDNF controls nerve cell production and survival
⦁ return the glutamate gene function to normal activity in the hippocampus. Glutamate is an amino acid, one of the twenty amino acids used to construct proteins, and as a consequence is found in high concentration in every part of the body. In the nervous system it plays a special additional role as a neurotransmitter: a chemical that nerve cells use to send signals to other cells. In fact glutamate is by a wide margin the most abundant neurotransmitter in the vertebrate nervous system. It is used by every major excitatory information-transmitting pathway in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It is no wonder that Cymbalta can cause such varied side effects and withdrawal symptoms as it can potentially effect all nerve cells in the brain and nervous system.
⦁ increase seratonin and noradrenaline levels in the spinal cord
⦁ have great effect on nerve cell growth, survival and death.
⦁ effect nitrous oxide levels in the brain.
⦁ decrease reuptake of dopamine
⦁ increase memory retrieval in the amygdala. (fear center in the brain)
⦁ effect the pons that relay signals from the forebrain to the cerebellum, along with nuclei that deal primarily with sleep, respiration, swallowing, bladder control, hearing, equilibrium, taste, eye movement, facial expressions, facial sensation, and posture.).
⦁ lower nerve growth factor concentrations
⦁ decrease the activity of the beta-actin mRNA Beta actin is used in muscle contractions.

http://www.cymbaltaw...elps#entry66904
Details and research on Cymbalta damage and effects.
AM - In extremely acidic conditions, or when a person's stomach contents move out of the stomach slowly, Cymbalta, unprotected by the enteric coating may undergo hydrolysis to form Naphthol. Caution is advised in using Cymbalta in patients with conditions thatmay slow gastric emptying." "Naphthol is found in pesticides and is toxic to lungs and mucous membranes. Repeated exposure to Naphthol may produce general deterioration of health by an accumulation in one or many human organs." "Naphthol may cause DNA damage to human lymphocytes."

https://dailymed.nlm...f2-c185fbad64ba
"In extremely acidic conditions, CYMBALTA, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using CYMBALTA in patients with conditions that may slow gastric emptying (e.g., some diabetics). "

http://www.cymbaltaw...age/?hl=caution
Damage caused by Cymbalta and other antidepressants.
------------------------------------------------------------------------------------------------------------

[fishinghat]

Effects of Cymbalta on the Body (cont)

Cymbalta and Alcohol

http://www.fda.gov/d...y/ucm088579.pdf
Page 5 of 6 from FDA
Use of Cymbalta concomitantly with heavy alcohol intake may be associated with severe liver injury. Avoid heavy alcohol use while taking Cymbalta.

The FDA site says that 0.46% of Cymbalta users reported increased alcohol consumption.

https://www.ncbi.nlm...pubmed/25161814
Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use.
Cymbalta lowers alcohol consumption.

https://www.ncbi.nlm...pubmed/18195589
Effects of naltrexone, duloxetine, and a corticotropin-releasing factor type 1 receptor antagonist on binge-like alcohol drinking in rats.
Decreased binge drinking in rats.

Note. The decrease in alcohol consumption would most likely not pertain to those suffering with mania and that is supported by looking at the alcohol related postings on this site where many report excessive consumption while being on Cymbalta.

Clonidine/Alcoholism
1) Clonidines effect on Alcohol consumption.
https://www.ncbi.nlm...pubmed/25085719
Alcohol. 2014 Sep;48(6):543-9. doi: 10.1016/j.alcohol.2014.07.002. Epub 2014 Jul 14.
The α2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats.
Clonidine significantly reduced alcohol intake.


https://www.ncbi.nlm...pubmed/15551068
Psychopharmacology (Berl). 2005 May;179(2):366-73. Epub 2004 Nov 17.
Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats.
To the degree that the present results are relevant to human alcoholism, alpha-2 adrencoceptor agonists should be considered in the treatment of alcohol dependence.

2) Clonidines effectiveness in treating alcohol withdrawal.
https://www.ncbi.nlm.../pubmed/3327372
Clonidine and alcohol withdrawal.
The alpha-2-adrenergic agonists in alcohol treatment seemed modestly effective for treatment of some parts of alcohol withdrawal.

https://www.ncbi.nlm.../pubmed/1969792
Drug Alcohol Depend. 1990 Feb;25(1):43-8.
The effect of clonidine and related substances on voluntary ethanol consumption in rats.
Clonidine, guanfacine and tiamenidine, in equihypotensive doses, significantly reduced alcohol intake in ethanol-preferring rats having free choice between 10% ethanol and drinking water. Water intake was only slightly reduced, especially during the first hours following the administration of clonidine. Simultaneous treatment with yohimbine attenuated the clonidine-induced reduction in ethanol intake. Putative central mechanisms underlying the observed inhibitory actions of clonidine and other alpha-2 adrenoceptor agonists on oral self-administration of alcohol are discussed.

https://www.ncbi.nlm...pubmed/21521867
https://www.ncbi.nlm.../pubmed/1103576
https://www.ncbi.nlm.../pubmed/7978098
https://www.ncbi.nlm.../pubmed/2646983
https://www.ncbi.nlm...pubmed/11091026
https://www.ncbi.nlm.../pubmed/6415735
https://www.ncbi.nlm.../pubmed/3300587
https://www.ncbi.nlm.../pubmed/3893195
https://www.ncbi.nlm.../pubmed/3441163
https://www.ncbi.nlm...pubmed/15551068
And many many more....

Hydroxyzine/alcoholism
There is no data on the use of hydroxyzine to reduce the desire/use of alcohol.
It has to be shown to not be effective in alcohol withdrawal.

Note - Neither clonidine nor hydroxyzine should be used WITH alcohol as it may cause a serious drop in blood pressure.
--------------------------------------------------------------------------------------------------------

[fishinghat]

Effects of Cymbalta on the Body (cont)

Cymbalta and Hyperglycemia

http://www.ehealthme...a/hyperglycemia
FDA and others number of reported cases of hyperglycemia

http://dailymed.nlm....F2-C185FBAD64BA
From NIH, a branch of the government.

http://www.ncbi.nlm....les/PMC3056054/
Research article on hyperglycemia.

http://www.accessdat...1427s030lbl.pdf
FDA reports of hyperglycemia.
------------------------------------------------------------------------------------------------------------
Mania/Sexual Effects while taking Cymbalta.

Please note that many of these articles relate the high risk mania as being related to bipolar disorder rather than Major Depression or Anxiety.

https://www.ncbi.nlm...pubmed/22024021
Persistent genital arousal disorder: successful treatment with duloxetine and pregabalin in two cases.
In both women, the treatment proved to be very successful over a long period of time. One of them experienced full remission (duloxetine) and the other one experienced substantial improvement (pregabalin), over a period now lasting for more than a year.

https://www.ncbi.nlm...pubmed/21091877
Sexual function during long-term duloxetine treatment in patients with recurrent major depressive disorder.
Cymbalta can cause sexual dysfunction (decreased sexual labido and performance).

https://www.ncbi.nlm...pubmed/17627739
Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder.
Same as above.

https://www.ncbi.nlm...pubmed/26003261
Psychiatric disorders and sexual dysfunction.
Same as above

https://dailymed.nlm...f2-c185fbad64ba

The following is from the drug insert information that come with Cymbalta.
5.8 Activation of Mania/Hypomania
In adult placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (4/3779) of CYMBALTA-treated patients and 0.04% (1/2536) of placebo-treated patients. No activation of mania or hypomania was reported in DPNP, GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, CYMBALTA should be used cautiously in patients with a history of mania.
Note - Mania is a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together with lability of affect." Symptoms include ...
⦁ Inflated self-esteem or grandiosity
⦁ Decreased need for sleep (e.g., feels rested after 3 hours of sleep.)
⦁ More talkative than usual or pressure to keep talking.
⦁ Flights of ideas or subjective experience that thoughts are racing. Increase in goal directed activity, or psychomotor acceleration.
⦁ Distractibility (too easily drawn to unimportant or irrelevant external stimuli).
⦁ Excessive involvement in activities with a high likelihood of painful consequences.(e.g., extravagant shopping, sexual adventures or improbable commercial schemes). Wiki

6.6 Effects on Male and Female Sexual Function in Adults
Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials patients treated with CYMBALTA experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with CYMBALTA experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on CYMBALTA than on placebo as measured by ASEX total score. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects.

http://www.gjpsy.uni...cle-mustafa.pdf
A Case of Possible Duloxetine-Induced Mania
"Her mood initially improved but two weeks into treatment she developed insomnia, hyperactivity and sexual arousal."

"Around the time of admission her symptoms constituted irritability, psychomotor agitation, pressure of speech, flight of ideas, insomnia, auditory and visual hallucinations, grandiose and persecutory delusions, aggressive and reckless behaviour, sexual disinhibition and lack of insight."


https://www.nami.org...tine-(Cymbalta)

The following is from the Nami data sheet on Cymbalta.
"Depression is also a part of bipolar illness. People with bipolar disorder who take antidepressants may be at risk for "switching" from depression into mania. Symptoms of mania include "high" or irritable mood, very high self esteem, decreased need for sleep, pressure to keep talking, racing thoughts, being easily distracted, frequently involved in activities with a large risk for bad consequences (for example, excessive buying sprees)."

http://www.mayoclini...ns/DRG-20067247

Some people may have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. If you or your caregiver notice any of these unwanted effects, tell your doctor right away.

----------------------------------------------------------------------------------------------------------

[fishinghat]

Effects of Cymbalta on the Body (cont)

Cymbalta and the Liver

https://dailymed.nlm...185fbad64ba#s23
Drug insert for Cymbalta
Section - 5.2 Hepatotoxicity (Liver toxicity)
"These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury."
"In most patients, the median time to detection of the transaminase elevation was about two months."
Note - More details on liver issues at this site.

https://www.ncbi.nlm...les/PMC3773985/
"All 6 patients recovered without liver transplantation even though 3 had pre-existing chronic liver disease."
"Duloxetine hepatotoxicity developed within 2 months of drug intake and led to clinically significant liver injury."

https://www.ncbi.nlm...ubmed/17257478/
'In a pooled analysis of 17,615 subjects, the incidence of serum alanine aminotransferase (ALT) levels > 3 times the upper limit of normal (ULN), > 5 ULN, and > 10 ULN were 1%, 0.5%, and 0.2%, respectively.5 Almost all subjects maintained normal values of alkaline phosphatase and total bilirubin with no case of jaundice and hepatocellular injury (“Hy’s law”) reported.'
https://www.ncbi.nlm...ubmed/18690992/
'However, post-marketing surveillance identified 406 cases with potential hepatotoxicity from duloxetine between 8/2004 and 8/2006.6 Of these, 58 cases were considered clinically significant. A careful review of these cases led to the following observations: (a) there was no dose-dependent increase in the incidence of hepatic injury, ( a large number of cases occurred between 2 and 8 weeks of therapy and 74% with onset within 16 weeks, © 31% had either pre-existing liver disease or clinical risk factors for liver disease, and (d) there were two fatal cases possibly related to duloxetine.'

https://www.ehealthm...balta/jaundice/
FDA statistics on side effects
"95,293 people reported to have side effects when taking Cymbalta.
Among them, 299 people (0.31%) have Jaundice"
Time on Cymbalta when people have Jaundice *:
⦁ < 1 month: 32.17 %
⦁ 1 - 6 months: 44.35 %
⦁ 6 - 12 months: 5.22 %
⦁ 1 - 2 years: 5.22 %
⦁ 2 - 5 years: 13.04 %
⦁ 5 - 10 years: 0.0 %
⦁ 10+ years: 0.0 %
-----------------------------------------------------------------------------------------------------------
Cymbalta and the Skin
https://dailymed.nlm...f2-c185fbad64ba
From the drug insert for Cymbalta...
(side effects) Also includes hypoaesthesia, hypoaesthesia facial, genital hypoaesthesia and paraesthesia oral (Soreness and sensativity in the mouth)
Severe Skin Reactions — Caution patients that CYMBALTA may cause serious skin reactions. This may need to be treated in a hospital and may be life-threatening. Counsel patients to call their doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions [see Warnings and Precautions ].
5.6 Severe Skin Reactions
Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with CYMBALTA. The reporting rate of SJS associated with CYMBALTA use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting.
CYMBALTA should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.

http://www.mayoclini...es/dxc-20317107
Details on SJS can be found at the above site.
Stevens-Johnson syndrome
Stevens-Johnson syndrome signs and symptoms include:
⦁ Fever
⦁ Unexplained widespread skin pain
⦁ A red or purple skin rash that spreads
⦁ Blisters on your skin and the mucous membranes of your mouth, nose, eyes and genitals
⦁ Shedding of your skin within days after blisters form
If you have Stevens-Johnson syndrome, several days before the rash develops you may experience:
⦁ Fever
⦁ Sore mouth and throat
⦁ Fatigue
⦁ Cough
⦁ Burning eyes
When to see a doctor
Stevens-Johnson syndrome requires immediate medical attention. Seek emergency medical care if you experience signs and symptoms of this condition.
------------------------------------------------------------------------------------------------------------

[fishinghat]

Effects of Cymbalta on the Body (cont)


Cymbalta, Seizures and Sodium

https://www.ncbi.nlm...les/PMC2963463/
We believe that this is the first reported case in which a person developed duloxetine withdrawal seizure secondary to deranged electrolytes after abruptly stopping duloxetine.
Her sodium was 134, potassium was 2.5, chloride 86, glucose 110, calcium 9, and magnesium 1.5.

https://www.ncbi.nlm...les/PMC3229538/
Although the risk of seizures with antidepressants is generally very low, the association with overdose is well established. However, the molecular mechanisms by which antidepressants cause seizures have not been clarified. GIRK2 knockout mice exhibit spontaneous seizures and are more susceptible to seizures induced by pentylenetetrazol than wild-type mice. The risk of seizures in overdoses with sertraline, duloxetine, mianserin, and venlafaxine significantly increases, and amoxapine overdose is more likely to cause seizures. Brain levels of the drugs in overdose cases may be considerably higher than levels during treatment at therapeutic doses, suggesting significant inhibition of neuronal GIRK channels by the drugs. Additionally, other types of K+ channels are inhibited by antidepressants at micromolar concentrations, that is, the two-pore-domain K+ channel, TREK-1 for sertraline and voltage-gated K+ channels for amoxapine and mianserin. Therefore, the inhibition of GIRK channels by the drugs after overdose together with the different types of K+ channels may contribute to increased seizure activity and the occurrence of other neurological side effects by increasing neuronal excitability.
Note - GIRK2 is a K+ ion regulatory mechinism.

https://www.ncbi.nlm...pubmed/16534127
Duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion and seizures.
Description of antidiuretic hormone
Kidney
Aantidiuretic hormone has three main effects:
Increasing the water permeability of initial and cortical collecting tubules and inner medullary collecting duct in the kidney, thus allowing water reabsorption and excretion of more concentrated urine, i.e., antidiuresis.
Increasing permeability of the inner medullary portion of the collecting duct to urea by regulating the cell surface expression of urea transporters, which facilitates its reabsorption into the medullary interstitium as it travels down the concentration gradient created by removing water from the connecting tubule, cortical collecting duct, and outer medullary collecting duct.
Acute increase of sodium absorption across the ascending loop of henle. This adds to the countercurrent multiplication which aids in proper water reabsorption later in the distal tubule and collecting duct.
Note - This could severely impact sodium and potassium levels in the blood stream.
From article - "We describe a woman who developed severe hyponatremia on exposure to duloxetine and recurrence on inadvertent rechallenge, suggesting the causative relationship of this drug to hyponatremia. "
Hyponatremia - is a low sodium level in the blood.
http://www.ncbi.nlm....pubmed/22306002
Generalized tonic-clonic seizure secondary to duloxetine poisoning: a short report with favorable out come.
Note - Tonic–clonic seizures (formerly known as grand mal seizures) are a type of generalized seizure that affects the entire brain. Tonic–clonic seizures are the seizure type most commonly associated with epilepsy and seizures in general, though it is a misconception that they are the only type.

https://www.ncbi.nlm...les/PMC2963463/
Duloxetine Withdrawal Seizure
She came to the emergency room with complaints of nausea, clear liquid vomitus, anxiety, “electical sensation” inside the body, restlessness, decreased liquid intake, abdominal pain, and decreased sleep. She stopped taking her duloxetine two days previoiusly. She had two generalized tonic clonic seizures 20 minutes apart in the hospital.

https://www.accessda...s011s013lbl.pdfFDA
Hyponatremia — Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported and appeared to be reversible when Cymbalta was discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.

Note this article links Cymbalta to Hyponatremia caused by inappropriate antidiuretic hormone secretion.
Medical research articles linking Cymbalta to Hyponatremia
http://www.ncbi.nlm....pubmed/23075738
https://www.ncbi.nlm...les/PMC3285747/
https://www.ehealthm.../hyponatraemia/
https://www.ncbi.nlm...pubmed/25538343
https://www.ncbi.nlm...pubmed/25911354
https://www.ncbi.nlm...pubmed/18562431
https://www.ncbi.nlm...pubmed/17224730
https://www.ncbi.nlm...pubmed/17502788

Comments by Members
Grand Mal Seizure And Mouth Spasms ?
Posted by justsayno on 02 April 2017 - 07:58 PM in How to Find Support
Was trying to work it out tonight. Looking for any patterns / similarities etc
Only obvious thing being that both seizures occurred after a dosage drop from 40 to 30 mg.

Grand Mal Seizure And Mouth Spasms ?
Posted by justsayno on 01 April 2017 - 02:26 PM in How to Find Support
Hi Gail
Far as I am aware No. In 28 years I've never had any seizures until I began taking Cymbalta.

Bead Counting Advice Doesn't Jive With My Capsule Contents
Posted by PtldFrank on 04 September 2016 - 04:44 PM in Weaning Off Cymbalta
Vinpin,
Regarding seizures, that's a subject I do have personal experience with. The good news is that I'm seizure free for more than 10 years. The bad news is that I had half a dozen gran mal seizures in the 12 years prior, starting with wellbutrin. I tend to believe the seizures all came from the various meds (15-20 combinations) I went through. The only thing that seems to have stopped the seizures is the anti seizure medicine Keppra.

[fishinghat]

Effects of Cymbalta on the Body (cont)

Involuntary Cold Turkey From 120Mg
Posted by Cassandra on 13 February 2015 - 10:32 AM in What are you feeling?
Hello world, this is Cassandra. It's been a rough month since I quit cymbalta and I think it'd be best to start from the very beginning.

I have been experiencing major depression as long as I can remember, at least from the age of 9 which is where my earliest memories are. I was put on my first antidepressant--celexa--5 or six years ago. I had been depressed before but when I started medication it just got worse. Five/six months ago I was put on cymbalta, first 60 mg then 120, and it got worse. I became violently suicidal and after a course of 12 ect treatments I attempted suicide by taking 2 bottles of cymbalta at once (my insurance had just switched me to where I could only get my meds in a 90 day supply--bad, bad idea to give someone who's suicidal a giant bag of meds.)

I woke up having seizures that went on for hours, and then on and off for a few days. When I got to the hospital, I was hallucinating, and couldn't stand or eat for days. I learned how to walk again and a month later I can ride my bike again.

Listing The Positive Events Daily Through My Cymbalta Withdrawl
Posted by FiveNotions on 24 December 2014 - 09:42 AM in ARE YOU NEW HERE? Words from the wise about Cymbalta
I was just talking with a friend about where I was last year this time ... compared to this year ... and it seemed more than worthy of a post in our "Positives" thread ...

Last year this time I was about 19 days into hard, cold turkey withdrawal ... I was overwhelmed with vertigo and nausea, confined almost totally to bed, and crawling to the bathroom to puke ... at one point, I just took my blanket and pillow in there and slept/lay curled up on the floor (less far to travel) ... I was unable to eat any solid foods, not even crackers ... and was living on broth and herb tea and water (didn't make for much to puke up, but I still did) ...
I was having constant muscle spasms, and had a couple of seizures (at least I assume that's what they were, I just blacked out and woke up on the floor) ... I was having auditory and visual hallucinations, constant cold, dripping sweats, and horrid general body aches and pains .... couldn't sleep much at all, just an hour or so at a time ... I hadn't showered, washed my hair, changed clothes, or changed my sheets, once ... and I simply did not care ...
Article: Duloxetine Withdrawal Seizure [Cold Turkey Withdrawal]
Posted by FiveNotions on 03 January 2015 - 09:32 AM in Cymbalta in the News
I think I had at least 1, possibly 2, seizures during hard, cold turkey withdrawal ... but don't know for sure, was alone and woke up on the floor ... yet another reason not to quit this poison cold turkey!
Duloxetine Withdrawal Seizure [full text]
Psychiatry (Sept 2006)
http://www.ncbi.nlm....les/PMC2963463/

From the article:

Much has been written about the use and side effects profile of duloxetine (Cymbalta®). We report a case of a patient who had generalized tonic clonic seizures after abruptly stopping duloxetine.

Case report. Ms. X was a 59-year-old Caucasian woman with a diagnosis of major depressive disorder recurrent severe without psychotic feature. She was stabilized on duloxetine 90mg p.o. daily.

She came to the emergency room with complaints of nausea, clear liquid vomitus, anxiety, “electical sensation” inside the body, restlessness, decreased liquid intake, abdominal pain, and decreased sleep.

She stopped taking her duloxetine two days previoiusly. She had two generalized tonic clonic seizures 20 minutes apart in the hospital.

Urine drug screen was negative. Urinalysis was negative. Complete blood count (CBC) was normal. Her sodium was 134, potassium was 2.5, chloride 86, glucose 110, calcium 9, and magnesium 1.5. Her blood urea nitrogen (BUN) and creatinine were normal. Her liver function tests were normal except mildly elevated alkaline phosphatase of 126. Computed tomography (CT) scan of her head was negative. There was no sign of infection at the point of admission. She was stabilized and was then started on a different antidepressant due to her history of nonadherence. She had no further seizures during her hospital stay.
Seizure?
Posted by sarahb on 04 April 2014 - 10:59 AM in What are you feeling?
My mother has been on Cymbalta I think 90mg and she recently started having seizures. I wonder if there could be any correlation. I'm the one who was on it 5 days and found your group and has decided to get off. Now my thoughts are with my mom. I know different things about her health are shorting her health but I hate to think what this drug is doing to her and God forbid she needs to get off.

And Here I Am- Am I Screwed Forever?
Posted by jenniesue on 09 December 2013 - 12:49 PM in ARE YOU NEW HERE? Words from the wise about Cymbalta
The DVT/Blood Clots were after I lost a pregnancy. Yes I was placed on Cymbalta for pain. The seizures I had started within 2 weeks of taking Cymbalta. Yes I have discussed all issues with my Dr. and they give me a diagnosis of something else, and have told me just keep taking the Cymbalta. Where do I start to get off of this evil med? I go to see my Dr. Monday Dec 15.

Seen The New Commercials?
Posted by Pixi on 10 June 2012 - 02:32 AM in Cymbalta in the News
I'd thought I was unsubscribed...but this thing emailed me for a reply so here goes. I can't believe it's almost a year to the day since I made the post on here. That means I've been totally Cymbalta free for 6 months! I took my healthcare into my own hands & I'm glad I had the fortitude to go through this & come out as well as I have.

I'm taking nothing for depression/neuropathy and still having the odd brain zap & dizziness - my "Cymbalta moments" as I call it. . Still having seizures at night, bouts of horrible dementia and just wish I'd never listened to the Doctors & allowed myself to be their labrat for this evil drug. Depression is still much better off it and bladder control is almost back to normal. The ONLY way to go is wean slowly, count the grains even tho it's tedious - over months, even if you're only just on it a few weeks, start to cut it down really slowly - your brain is way more delicate than you know. This shit does pretty weird things to you - that's how it's supposed to work - alter your neurology. Don't let them mess with you. It caused me DID/MPD, made my diabetic neuropathy 100 times worse & a host of other shit I've probably posted about elsewhere on this forum.

Seizures From Cymbalta
Posted by Namaste on 02 May 2012 - 02:04 AM in Weaning Off Cymbalta
Doctor changed celexa to cymbalta And was ok with it for a month and
I started Having hives, itching and bruises. My doctor stopped cymbalta and gave me prednisone. Then i started having seizures where i was fully aware of what was happening so I'm now on lamictal for seizures. Anyone of you having the same experience?
My Chapter Of Hell
Posted by distill on 06 December 2011 - 02:55 AM in ARE YOU NEW HERE? Words from the wise about Cymbalta
I have already wrote this once, but if I can help out another person then I've done what I set out to do.

I know some people have done great while taking it but the withdrawal is what gets them. I was not depressed, I was injured on the job crush three disc in my lower back. I was put on it for sciatic help.

I had a house, cars, and my best friend for a fiance. Within two weeks of taking it I lost my mind. Manic aggression, seizures, nightmares, etc. I did things I never wouldve done before this. Its like i either knew what i was doing and didnt care or i flat out dont remember. We were losing the house and my demeanor drove her away. Workers comp denied paying for all psychological meds and I flat out couldn't afford $400 for 90days. That was in January of this year.
Neuropathy As A Side Effect?
Posted by cookie on 28 November 2011 - 11:57 AM in Weaning Off Cymbalta
Dear Pixi

I took cymbalta for depression, other than than I was a pretty healthy person. After 6 years of taking it, I have sugar problems and now I am experiencing prickling sensations and pin & needles. I also have problems remembering names. I also experienced seizures and problems with my joints which I never had prior to the medication

Check In On Your Progress Here!
Posted by CindiEponabri on 16 October 2011 - 01:31 AM in Weaning Off Cymbalta
1) Method you're using
Counting bead method, kinda... I take out about 1/4 of the beads out of one of the two capsules for each day's dosage, for a week. The following week it will be 1/2 of the beads of one capsule.

2) Starting dose
120mg

3) Current dose
105mg (roughly)

4) Withdrawal symptoms you're having
more pain, anxiety, dizziness, tired, nausea, cold/flu symptoms, nightmares, itching,


5) Things that have improved.
Seizures.. we had thought they were being caused from the Oxycotin, but now I see it was from the Cymbalta, because for the most part they are now gone. I have a little one every now and then.

My Story
Posted by cookie on 26 July 2011 - 02:25 PM in Weaning Off Cymbalta
Dear Imdone:
.....However I learned to differentiate the initiall symptoms from withdrawals. I took the medication for severe depression. When I reduced dose I started experiencing asthma, itching, joint pain, problems finding words to talk and comprehending language, dizziness, vomiting, seizures, facial tics, sensitivity to noises and light, tremors, allergies, sore throat, etc which I definitely didn´t have when my depression appeared 6 years ago.

[fishinghat]

Effects of Cymbalta on the Body (cont)

Drug insert from Eli Lilley for Cymbalta
https://dailymed.nlm...f2-c185fbad64ba

5.7 Discontinuation of Treatment with CYMBALTA
Discontinuation symptoms have been systematically evaluated in patients taking CYMBALTA. Following abrupt or tapered discontinuation in adult placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in CYMBALTA-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.
During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.
Patients should be monitored for these symptoms when discontinuing treatment with CYMBALTA. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.7)].
6.12 Postmarketing Spontaneous Reports
The following adverse reactions have been identified during post approval use of CYMBALTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions reported since market introduction ....., seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.
Medical Research on Seizures and Cymbalta.
Other info on seizures,

https://www.ncbi.nlm...les/PMC3229538/
"Although the risk of seizures with antidepressants is generally very low, the association with overdose is well established [80]. However, the molecular mechanisms by which antidepressants cause seizures have not been clarified. GIRK2 knockout mice exhibit spontaneous seizures and are more susceptible to seizures induced by pentylenetetrazol than wild-type mice . The risk of seizures in overdoses with sertraline, duloxetine, mianserin, and venlafaxine significantly increases, and amoxapine overdose is more likely to cause seizures. "
80. Montgomery SA. Antidepressants and seizures: emphasis on newer agents and clinical implications. Int J Clin Pract. 2005;59:1435–1440. [PubMed]
81. Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Q J Med. 2003;96:369–374. [PubMed]
82. Isbister GK, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004;42:277–285. [PubMed]

https://www.ncbi.nlm...les/PMC4683813/
"Epilepsy is a serious condition which can profoundly affect an individual’s life. While there is some evidence to suggest an association between antidepressant use and epilepsy and seizures it is conflicting and not conclusive. "
"Conclusions
Risk of epilepsy/seizures is significantly increased for all classes of antidepressant. There is a need for individual risk-benefit assessments in patients being considered for antidepressant treatment, especially those with ongoing mild depression or with additional risk factors. Residual confounding and indication bias may influence our results, so confirmation may be required from additional studies."

https://www.ncbi.nlm...pubmed/16534127
Neurology. 2006 Mar 14;66(5):773-4.
Duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion and seizures.
Maramattom BV1.
"The syndrome of inappropriate antidiuretic hormone secretion (SIADH) and hyponatremia is a well known side effect of older selective serotonin reuptake inhibitors (SSRIs) such as paroxetine, sertraline, fluoxetine, citalopram, escitalopram, and fluvoxamine.1,2 The frequency of hyponatremia is around 8 per 1,000 among elderly women receiving fluoxetine.2 Although the second-generation dual blockers, selective serotonin–norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine, are touted to have a wider therapeutic index, hyponatremia is encountered even with venlafaxine. To date, Medline searches do not reveal any reports of hyponatremia associated with duloxetine. We describe a woman who developed severe hyponatremia on exposure to duloxetine and recurrence on inadvertent rechallenge, suggesting the causative relationship of this drug to hyponatremia. "


http://www.psychforu...topic69139.html
This is a thread about seizures and Cymbalta you might want to check out.

http://www.ehealthme...mbalta/seizure/
95,293 people reported to have side effects when taking Cymbalta.
Among them, 1,077 people (1.13%) have Seizures

https://www.ncbi.nlm...pubmed/16534127
Duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion and seizures.
http://www.ncbi.nlm....pubmed/22306002
Generalized tonic-clonic seizure secondary to duloxetine poisoning: a short report with favorable out come.
Abstract
Duloxetine is a potent and selective inhibitor of serotonin and norepinephrine reuptake (SNRI) with a weak activity over dopamine reuptake used in the treatment of major depressive disorder. Daily doses of 60 mg are effective in treatment of major depression. There are few cases of isolated duloxetine overdose in humans. We think this is the first report of a generalized tonic-clonic seizure following isolated duloxetine poisoning with a very high dosage.

https://www.ncbi.nlm...les/PMC2963463/
Duloxetine Withdrawal Seizure
She came to the emergency room with complaints of nausea, clear liquid vomitus, anxiety, “electical sensation” inside the body, restlessness, decreased liquid intake, abdominal pain, and decreased sleep. She stopped taking her duloxetine two days previoiusly. She had two generalized tonic clonic seizures 20 minutes apart in the hospital.

Drugs.com
Applies to: Wellbutrin (bupropion), Cymbalta (duloxetine)
Talk to your doctor before using buPROPion together with DULoxetine. Combining these medications may increase the risk of seizures, which may occur rarely with either medication. In addition, buPROPion can increase the blood levels of DULoxetine, which may increase other side effects. You may be more likely to experience seizures with these medications if you are elderly, undergoing alcohol or drug withdrawal, have a history of seizures, or have a condition affecting the central nervous system such as a brain tumor or head trauma.
"Early in my treatment for CFSi, my doctor prescribed both Cymbalta (duloxetine) and Wellbutrin (bupropion). Although not listed in this table, you can find from Dr. Flockhart’s tables that bupropion is a strong inhibitor of the 2D6 enzyme used to metabolize duloxetine. Combine this interaction with the possibility that I am one the 10% of Caucasians who are slow 2D6 metabolizers, and you have a plausible explanation why after a few months duloxetine became toxic for me to take. Recently on the cpnhelp.org site, "

Lamictal - The subjective evidence is overwhelming in the blogs and forums as well as in advertisements for drug withdrawal programs that there is Lamictal withdrawal although as you may notice not a lot of medical research on this subject. Lamictal is often prescribed to Cymbalta patients if they develop seizures.
I also noticed that it is approved for seizures and not as an antidepressant as it is rarely effective on this condition.
https://www.ncbi.nlm...pubmed/21881472
"Immediately following the abrupt discontinuation of lamotrigine, RBD symptomatology was severely aggravated, with dreams becoming more vivid and frightening and occurring almost every night. RBD symptomatology gradually subsided over 2 months, reaching levels comparable to those before lamotrigine."

https://www.ncbi.nlm...pubmed/11886370
"Withdrawal syndrome caused by anti-epileptic drugs has been rarely reported. However, in our personal experience of patients monitored for epilepsy surgery, many patients complained of minor reactions when the treatments were quickly decreased. Severe reactions are exceptional and may be explained in this case by the pharmacodynamic effects of LTG. It has indeed been suggested that LTG could have psychostimulant and antidepressive effects."

https://dailymed.nlm...ed-762cbea0d737
From the drug insert from the manufacturer.
Discontinuation Strategy
Epilepsy: For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.
If a decision is made to discontinue therapy with lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].
Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.
Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. Discontinuation of lamotrigine should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions ].

https://www.fda.gov/...s/ucm454864.pdf
From the FDA
Withdrawal and Rebound
Withdrawal and rebound were assessed during Trial SCA102833 by monitoring AEs in the OL and Double-blind Taper Phases. Few AEs were reported during the Taper Phases. In the OL Taper Phase, 14 (40%) subjects reported AEs. AEs reported in ≥5% of subjects included headache (20%), somnolence (6%), and suicidal ideation (6%). All
other AEs were reported in ≤5% of subjects.
In the Double-Blind Taper Phase, 18 (34%) subjects in the LTG group and 14 (25%) in the PBO group reported AEs. Headache was the only AE reported in ≥5% (8% in the LTG group and 7% in the PBO group). All other AEs were reported in ≤5% of subjects. One (3%) SAE was reported in the OL Taper Phase (bipolar disorder) and 2 (3%) subjects reported SAEs in the Double-blind Taper Phase (infectious mononucleosis,
152 Reference ID: 3702139 Clinical Review Francis E. Becker, M.D. NDA 22251 SD-220, 20764 SD-545, 20241 SD-1541 Lamictal (lamotrigine)
urinary tract infection, and suicidal ideation). Both of the subjects in the Double-blind Taper Phase were in the PBO group.
No seizures were reported in the taper phases of Trial SCA102833, however as with other AEDs, Lamictal should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in adult subjects with BPD, 2 subjects experienced seizures shortly after abrupt withdrawal of Lamictal; however, there were confounding factors that may have contributed to the occurrence of seizures in these BPD subjects. Unless safety concerns require a more rapid withdrawal, the dose of Lamictal should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) (see Lamictal Prescribing Information).
https://www.fda.gov/...ew summary).pdf
From FDA
LAM20006 was a randomized, double-blind, placebo-controlled parallel-group study. It
followed an enrichment design. Patients were first enrolled in an open-label period.
Lamictal was added on to existing therapy (patients could be taking 1-2 concomitant
AEDs) and seizure diary data was collected. Patients who demonstrated a protocolspecified
percent reduction in seizures during this phase were eligible to be randomized
to 1) continue Lamictal, or 2) undergo a gradual withdrawal to placebo. The withdrawal
occurred over 3 weeks with a 25% reduction in dose each week (75%, 50%, 25%, then
discontinue). The double-blind phase that followed lasted 8 weeks.
https://www.fda.gov/...e/ucm234471.pdf
Mild thrombocytosis has been reported in some infants and withdrawal symptoms can occur if breastfeeding is abruptly discontinued.

Misc.
Benzos can trigger seizures.
------------------------------------------------------------------------------------------------------------

[fishinghat]

Effects of Cymbalta on the Body (cont)

Hyponatremia
Note - Hyponatremia is a know cause of grand mal seizures, but low potassium is not. Cymbalta can cause Hyponatremia (low serum sodium levels). See below
https://www.accessda...s011s013lbl.pdfFDA
Hyponatremia — Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported and appeared to be reversible when Cymbalta was discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.

http://www.ncbi.nlm....pubmed/23075738
A case of severe hyponatremia induced by duloxetine and ziprasidone.

https://www.ncbi.nlm...les/PMC3285747/
Rapid-Onset Hyponatremia Induced by Duloxetine in a Middle-Aged Male with Depression and Somatic Symptoms

https://www.ehealthm.../hyponatraemia/
95,293 people reported to have side effects when taking Cymbalta.
Among them, 649 people (0.68%) have Hyponatraemia

https://www.ncbi.nlm...pubmed/25538343
Duloxetine-induced hyponatremia in an elderly patient treated with thiazide diuretics.

https://www.ncbi.nlm...pubmed/25911354
Syndrome of inappropriate antidiuretic hormone secretion: a story of duloxetine-induced hyponatraemia.

https://www.ncbi.nlm...pubmed/18562431
Severe and symptomatic hyponatremia following duloxetine treatment.

https://www.ncbi.nlm...pubmed/17224730
Duloxetine and hyponatremia: a report of 5 cases.

https://www.ncbi.nlm...pubmed/17502788
Recurrent hyponatremia after substitution of citalopram with duloxetine.
And more....

https://www.mayoclin...ms/con-20031445
Mayo Clinic
Hyponatremia signs and symptoms may include:
⦁ Nausea and vomiting
⦁ Headache
⦁ Confusion
⦁ Loss of energy and fatigue
⦁ Restlessness and irritability
⦁ Muscle weakness, spasms or cramps
⦁ Seizures
⦁ Coma
------------------------------------------------------------------------------------------------------------Cymbalta's Effect on Neurotranmitters in the Brain.

http://www.ncbi.nlm....les/PMC2626928/

http://www.ncbi.nlm....pubmed/18751896

http://www.ncbi.nlm....pubmed/15991911

http://www.ncbi.nlm..../pubmed/8592129

http://www.ncbi.nlm..../pubmed/7576005

-----------------------------------------------------------------------------------------------------------

[fishinghat]

Cymbalta Fat Soluble & Tissue Absorbtion.

From:
http://www.drugs.com/pro/cymbalta.html
"Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water."
Note - From the structure we can see that the compound is primarily non-polar and therefore should be fat soluble.

From:
http://www.drugbank.ca/drugs/DB00476
Water Solubility = 0.00296 mg/mL (Vertually insoluble)
Note - If it is not water suluble (polar (has a negative or positive charge)) then it is non-polar (not charged) and would be lipid soluble.

From:
http://www.selleckch...l-cymbalta.html
Chemical Information
Solubility (25°C) * In vitro DMSO 67 mg/mL (200.67 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)

Note - Dissolves well in DMSO a relatively nonpolar solvent.

From:
http://toxwiki.wikis....com/Duloxetine
Soluble in dimethylformamide (nonpolar) and water.

From:
https://www.ncbi.nlm...les/PMC3299448/
Table I
Amount of Solid Lipid (fat) Required to Solubilize 20 mg of DLX and Percent Partitioning of DLX in Lipid vs Water
Solid lipid Amount (mg) % Partitioning
Glyceryl monostearates 400 92
Glyceryl behenate 700 33
Glyceryl palmitostearate 650 60
Geleol 450 60
Gelucire 44/14 800 –

From 33% to 92% lipid (fat) soluble.
Ta
http://www.ema.europ...776.pdfstmortem

Tissue

Duloxetine was highly bound to proteins in plasma, the mean percent bound to human plasma proteins at a duloxetine concentration of 150.2 ng/mL being 95.9%.

Duloxetine was present in high concentrations in the stomach and intestinal contents at 3 to 12 hours postdose. Kidney, liver, and lung contained the highest tissue concentrations. Overall, the liver was determined to be the primary organ
responsible for the metabolism of duloxetine.Distribution of Duloxetine
------------------------------------------------------------------------------------------------------------