145 replies to this topic

[fishinghat]

Repetitive Transcranial Magnetic Stimulation (rTMS).

Transcranial magnetic stimulation (TMS) is a method in which a changing magnetic field is used to cause electric current to flow in a small region of the brain via electromagnetic induction. During a TMS procedure, a magnetic field generator, or "coil", is placed near the head of the person receiving the treatment. The coil is connected to a pulse generator, or stimulator, that delivers a changing electric current to the coil
Wiki

Anxiety

Left DLPFC rTMS stimulation reduced the anxiety bias effect or how to restore the positive memory processing in high-anxiety subjects.
Reduced anxiety

https://www.ncbi.nlm...pubmed/24081515
[Repetitive transcranial magnetic stimulation (rTMS) for anxiety disorders--a possible therapeutic option?].
Beneficial

https://www.ncbi.nlm...pubmed/25659132
Repetitive transcranial magnetic stimulation ameliorates anxiety-like behavior and impaired sensorimotor gating in a rat model of post-traumatic stress disorder.
Helped

https://www.ncbi.nlm...pubmed/24278088
Repetitive Transcranial Magnetic Stimulation (rTMS) to Treat Social Anxiety Disorder: Case Reports and a Review of the Literature.
Helped

https://www.ncbi.nlm...pubmed/22528734
rTMS stimulation on left DLPFC affects emotional cue retrieval as a function of anxiety level and gender.
Helped

https://www.ncbi.nlm...pubmed/20599325
Baseline 'state anxiety' influences HPA-axis sensitivity to one sham-controlled HF-rTMS session applied to the right dorsolateral prefrontal cortex.
Inconclusive

https://www.ncbi.nlm...pubmed/21631403
The value of repetitive transcranial magnetic stimulation (rTMS) for the treatment of anxiety disorders: an integrative review.
No conclusive evidence it helps.

https://www.ncbi.nlm...pubmed/24923343
Repetitive transcranial magnetic stimulation (rTMS) to treat refractory panic disorder patient: a case report.
Helped

https://www.ncbi.nlm...pubmed/23683151
Repeated transcranial magnetic stimulation on dorsolateral prefrontal cortex improves performance in emotional memory retrieval as a function of level of anxiety and stimulus valence.
"might limit" anxiety

https://www.ncbi.nlm...pubmed/24757668
Does rTMS alter neurocognitive functioning in patients with panic disorder/agoraphobia? An fNIRS-based investigation of prefrontal activation during a cognitive task and its modulation via sham-controlled rTMS.
No benefit

https://www.ncbi.nlm...pubmed/26843373
Better than treated as usual: Transcranial magnetic stimulation augmentation in selective serotonin reuptake inhibitor-refractory obsessive-compulsive disorder, mini-review and pilot open-label trial.
2/3 of current ssri treated group showed further improvement.

https://www.ncbi.nlm...pubmed/25565694
Repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex for treating posttraumatic stress disorder: an exploratory meta-analysis of randomized, double-blind and sham-controlled trials.
"seems to be effective and acceptable for treating PTSD"

https://www.ncbi.nlm...pubmed/18572984
A preliminary study of fMRI-guided rTMS in the treatment of generalized anxiety disorder.
Effective

Depression

https://www.ncbi.nlm...pubmed/22653158
Low-frequency rTMS over right dorsolateral prefrontal cortex in the treatment of resistant depression: cognitive improvement is independent from clinical response, resting motor threshold is related to clinical response.
42.9% showed an improvement in depression.

https://www.ncbi.nlm...m=Choi KM, rTMS
The effects of 3 weeks of rTMS treatment on P200 amplitude in patients with depression.
Helped

https://www.ncbi.nlm...pubmed/23291399
Are neuroticism and extraversion associated with the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS)? An exploratory 4-week trial.
Decreases depression.

https://www.ncbi.nlm...pubmed/25683231
Durability OF the antidepressant effect of the high-frequency repetitive transcranial magnetic stimulation (rTMS) In the absence of maintenance treatment in major depression: a systematic review and meta-analysis of 16 double-blind, randomized, sham-controlled trials.
Slightly helpful

https://www.ncbi.nlm...pubmed/23928104
Antidepressant efficacy of high and low frequency rTMS at 110% of motor threshold versus sham stimulation over left prefrontal cortex.
Helps

Anxiety and depression.

https://www.ncbi.nlm...m=White D, rTMS
Repetitive transcranial magnetic stimulation for treatment of major depressive disorder with comorbid generalized anxiety disorder.
Helpful for both Anxiety AND depression.

Dozens and dozens of other articles which also showed it helped some, inconclusive, use as additional therapy. and didn't help. Really a mixed bag.

Members Comments

One member has actually tried this procedure for anxiety. His treatments lasted 6 weeks and he stated there was no sign of improvement. A second member tried this method and did not find it helpful plus developed a lot of side effects.
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[fishinghat]

ECT - Electroconvulsive therapy
Electroconvulsive therapy (ECT), formerly known as electroshock therapy, and often referred to as shock treatment, is a psychiagtric treatment in which seizures are electrically induced in patients to provide relief from mental disorders. Wiki
https://www.mayoclin...ut/pac-20393894
Mayo Clinic overview of ECT. Not used for anxiety.

https://www.ncbi.nlm...pubmed/25830809
A clinically significant improvement was observed for 10 (77%) adolescents receiving ECT for treatment-resistant depression.

https://www.ncbi.nlm...pubmed/23291702
Electroconvulsive therapy may improve symptoms of comorbid body dysmorphic disorder along with mood improvement in treatment-resistant depressive disorder.

https://www.ncbi.nlm...pubmed/23349112
reduction of depressive symptomatology was significantly more pronounced in the ECT group over the rTMS group.
Very limited research
Members Comments
3 members mention having had ECT but don't really mention the final success or failure.
SK8mama - Did you go through with the ECT? Did you qualify for it with the BP II? I did ECT in 2016. I had been hospitalized for severe depression, and my depression is treatment resistant and had many medication failures. ECT also did not work for me, and it has some cognitive side effects, and I had increased paranoia and anxiety. But it also did not help that for one of my treatments, I was not fully under anesthesia and was awake and remember portions of it, so I ended up with PTSD,
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Feedback Mechanisms
Neurofeedback
Neurofeedback (NFB), also called neurotherapy or neurobiofeedback, is a type of biofeedback that uses real-time displays of brain activity—most commonly electroencephalography (EEG), to teach self-regulation of brain function. Typically, sensors are placed on the scalp to measure activity, with measurements displayed using video displays or sound.
Juli - when i reinstated from cold turkey but was feeling like crap for 8 weeks i started neurofeedback and it really helped. it seemed to get my brain back on track and helped with the nausea and anxiety. might be worth a try.
ThisMoment - Taking your temperature with a thermometer is a form of biofeedback. You can listen to your heartbeat via a stethoscope and actually cause it to slow down- that's an example of neurofeedback.
Neurofeedback or neurobiofeedback- There is a "normal" pattern of brain activity for a person's gender and age. There are a number of different EEG brain signatures for depression, ADD, and anxiety (for example), and your EEG is compared to those-- this is called a Quantitative Electroencephalogram or QEEG. Then it's determined what type of neurofeedback therapy would benefit you most. You are hooked up to the machine via scalp probes, and on a screen you view brainwave representative patterns with which you interface and alter directly. Do it enough (practice) and your brain changes.
This technology has supporters and critics. I don't know enough about it to offer criticism of the service, but I do think that when you include the whole body and all of your senses in real situations when training your brain, the result is always authentic, profound, and long-lasting.
Xanaxul - This is basically what neurofeedback does: to use the "gates" to our brain, that our senses are, to try the reshaping of discrete regions thus "normalizing" brain functions.
In my opinion, despite the "scientific apparel" it is clothed (EEG responses to the positive or negative stimuli, pinpointing of the brain areas...) it has not much advantages, over any other empirical methods (including the century old ones) that may be used to influence brainwave entrainment, brain connections reshaping or the volume and density of brain areas involved in cognition, mood and emotion processing.

But again, this is just my opinion.

We know so little about how our brain works, that I guess for the moment: "if it makes you feel better do it" has to be the motto.

ThisMoment - Here's a concern: The process of discontinuation will change your brain, and some of the progress achieved via the neurofeedback may be lost (or irrelevant) due to the changing landscape of your brain. Perhaps consider reducing or stopping the neurofeedback sessions until you are free and clear of the re-construction project in your brain. Then go back in with a more stable platform.

Greenpurple - You are right- Neurofeedback is so expensive! I am blessed to be able to afford some of it. And so is Cymbalta/Duloxetine. No wonder folks are so mad!!

Now that I've begun the neurofeedback road, I am so excited to see what is possible getting off my medsor reducing. I'm curious if I've been experiencing some of the side effects you all have been experiencing without knowing it. I've already forked out quite a bit of money (inheritance) and so can't afford unlimited neurofeedback but want to go off Cymbalta sloooooooowly, like everyone here has recommended. I went down from 90
To 60mg, no prob. Then started pellet counting as so many have recommended. I've cut down 10% each month (very sloooowwwww). Now I am down to 153 pellets and am quite proud of that! And I'm feeling great.

I think I may be cutting down too slowly if I am doing neurofeedback. At this rate, it would take me 360 more sessions (neurofeedback 2x per week and cutting 10% each month)!!!! That is absolutely impossible financially. Even twice as fast isn't a possibility (180 sessions)!

[fishinghat]

Feedback Mechanisms (cont)

Does anyone have an idea how quickly I could cut down with minimal withdrawals while doing neurofeedback???

Geff - I have to say the Neurofeedback made a HUGE change in my outlook! I am FINALLY able to concentrate and focus (which is important as I'm a computer programmer).

Just in case you (or anyone else reading your blog) isn't familiar with Neurofeedback, here's a quick description:

My therapist hooks up some sensors to my head and a computer program reads the electrical signals my brain is producing. It does NOT send any signals, shocks, etc.... just reads what my brain is doing. When my brain produces signals that are good, the computer goes *BING*. I guess my brain likes that because it starts trying to make it go *BING* more. The end result is that my brain is "trained" to work the way it should.
It was so cool the first session when she hooked me up and told me what she was seeing (I have a screen, too, to see what the program is reading). She was able to compare my brain activity to that of a "normal" brain and describe why I felt so down and had so much trouble focusing.
The only side-effects I've had are:
1. a very slight headache that goes away shortly after the treatment
2. better mood
3. better concentration
4. better productivity

Juli - 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.


Biofeedback

Guest_crushynn - A couple weeks after starting Cymbalta I started seeing a nutritionist & biofeedback person which has helped me soooo much as far as energy, focus, digestion, mood & weight. I noticed the Cymbalta wasn't working as well after a couple months & since I was doing so well with biofeedback & supplements, I decided to wean off Cymbalta about 3 weeks ago. I was only taking 30mg/ day to begin with so the withdrawals are amazing to me.

Imdone - In the meanwhile, consider meditation to give you control over anxiety. Biofeedback (covered by insurance) is another way to control anxiety.

Research

https://www.ncbi.nlm...pubmed/29432505
Psychiatr Pol. 2017 Dec 30;51(6):1095-1106. doi: 10.12740/PP/68919. Epub 2017 Dec 30.
The use of EEG Biofeedback/Neurofeedback in psychiatric rehabilitation.
Its psychiatric applications for clinically diagnosed disorders include treatmentof depression, anorexia, dyslexia, dysgraphia, ADD, ADHD, schizophrenia, abuse of substances, neuroses, PTSD, and Alzheimer's disease. Research results imply that the neuromodulating effect of the therapy positively influences cognitive processes, mood, and anxiety levels. Positive effects of EEG Biofeedback confirm usefulness of this method as a main or auxiliary method in treatment of people with mental disorders. On the basis of conducted studies, it is worthwhile to consider inclusion of this method into the comprehensive neurorehabilitation activities.

https://www.ncbi.nlm...pubmed/28236680
Behav Res Ther. 2017 May;92:32-40. doi: 10.1016/j.brat.2017.02.002. Epub 2017 Feb 20.
Frontal alpha asymmetry neurofeedback for the reduction of negative affect and anxiety.
The asymmetry group showed an increase in alpha asymmetry driven by higher alpha at the right site (p < 0.001), as well as a coherent reduction in both negative affect and anxiety symptoms (ps < 0.05), from pre-to post-training. No training-specific modulation emerged for positive affect and depressive symptoms. These findings provide a strong rationale for the use of frontal alpha asymmetry neurofeedback for the reduction of negative affect and anxiety in clinical settings.

https://www.ncbi.nlm...pubmed/25411662
Neurofeedback and Biofeedback for Mood and Anxiety Disorders: A Review of the Clinical Evidence and Guidelines – An Update [Internet].
Source
Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2014 Aug.
CADTH Rapid Response Reports.
CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING
Similar to the original CADTH review, evidence regarding the use of biofeedback for treatment of post-traumatic stress disorder or depression came mostly from pilot and exploratory studies with preliminary analyses ranging in size from 11 to 100 participants. HRV biofeedback was commonly evaluated in the newer clinical trials, and it was found to be associated with improvement in PTSD symptoms and depression symptoms: in one systematic review of patients with posttraumatic stress disorder, HRV biofeedback therapy was not shown to be better than unspecified usual treatment, but in an observational study of depressive patients, it had statistically significant benefit over usual care (such as morning exercise and social activities). One RCT implied the possible clinical benefits of HRV biofeedback therapy over a sham control in patients with depression; however a statistically significant between-group difference was not detected in this small patient group. Furthermore, the clinical relevance of an observed between-group difference was uncertain due to the lack of minimal clinically important difference for the employed clinical scales. No evidence on the use of biofeedback or neurofeedback in patients with generalized anxiety disorder was identified. Compelling evidence from larger scale randomized controlled trials with alternative therapies as the comparator is still needed to confirm the potential of biofeedback and neurofeedback, and to develop guidelines regarding the use of these non-pharmacological and non-invasive modalities for the treatment of mood and anxiety disorders.
Several more research articles exist. Most are of small small size and conflicting results.

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[fishinghat]

NAMI - National Alliance on Mental Illness
NAMI is a mental illness support organization which provides education, support groups and advice to mental illness patients and their families, churches and schools. Some offices will recommend psychiatrists and psycologists.
https://www.nami.org/Organization's Website
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Area Agencies for Aging
As a result of the 1973 amendments to the federal Older Americans Act (OAA), states were required to divide their state into planning and service areas, and to designate Area Agencies on Aging (AAA) to develop and implement programs and services for older persons at the local level.
My local agency can provide medical devices for loan without charge. Also provide assistance to disabled and older adults who need help with cooking, house cleaning, taken to the drs, listening/companionship and so much more. Depending on the need their may be no charge for surfaces (if they have enough volunteers) or a minimal hourly fee. They also have special programs for the disabled, mentally ill, home bound, veterans and will help with referals to other local support agencies including financial aide groups.
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[KathyInFL]

You are awesome, Dr Hat!! 

[fishinghat]

Peripheral neuropathy

https://www.cymbalta...upplementation/

Sk8rmama24 -I did some research, found a few recommended vitamins, minerals, supplements, etc, so I thought I would share some of what I have found.
Omega 3 Supplements
I have taken these before, and researched the optimal doses and formulations for Omega 3s as they related to being used to augment treatment for depression or ADHD. This supplement also seems to help with brain zaps from what I have read on other forums. The ratio of EPA/DHA has been examined and found to be pretty important in the overall efficacy of the supplement. These are the two Omega 3 supplements I have selected for 1) most cost effective, 2) most potency in smallest possible dosage, 3) optimal EPA/DHA ratio and 4) least fishy smell and burpless. I prefer the Bioscience Nutrition brand. I am sure there are other good formulations available, but these are ones I use.
⦁ Bioscience Nutrition (now Arazo Nutrition) Triple Strength Omega 3 Fish Oil: 2250mg omega 3s (1200mg EPA/900mg DHA) - 3 softgels
⦁ Bronson Omega 3 Fish Oil Triple Strength: 2720mg (1250mg EPA/ 488mg DHA) - 2 softgels
Neurovascular Support/Nerve Health/Brain Health Supplements
There are a variety of supplements out there formulated for nerve health and to ease neuropathy. I did a search for recommended and effective supplements and looked up information regarding each component of a neuro-health supplement. The top most recommended components include:
⦁ alpha lipoic acid (generally safe evaluated dose for neuropathy-600mg)
⦁ benfotiamine (B1 vitamin) (generally safe evaluated dose- 300-600mg)
⦁ acetyl L-carnitine (generally safe evaluated dose - 500mg)
⦁ N-acetyl Cysteine (1200mg 1-2 times a day, start lower and increase)
⦁ resveratrol (dose clinically evaluated from 500-1000mg, side effects at higher doses)
⦁ evening primrose oil (recommended dose-500mg)
⦁ curcumin (recommended dose- 500-1000mg, start lower and increase, do not take within 4 hours of medications, multiple precautions)
The different formulations also contain B vitamin, calcium, magnesium, chromium, glucosamine, etc. Dosages and ingredients really vary by manufacturer, and I am still researching the most cost effective formulation in this category, I will post my findings later. Before taking any formulated supplement, ALWAYS READ THE INGREDIENTS AND DOSES! There is such a broad array of formulations, some contain subtherapeutic doses, some contain an excess in doses, and if you take multiple supplements or vitamins, double check the total dose you are consuming with all supplements because many formulations contain B, D, C, calcium, magnesium. Some excess vitamin or mineral may be excreted as unused waste, but some become toxic at higher doses or require blood concentration monitoring.
https://www.salubrainous.comhas a good and easy to read explanation, scientific references, and precautions for various supplements. I found it useful.

[fishinghat]

Peripheral neuropathy (cont)

Vitamins and Minerals
There are also some recommended vitamins and minerals for neuro, immune and metabolism/mithochondrial health.
⦁ B vitamins
⦁ ​​B1, B2, B3, B5, B6, B7, B9, B12 (may interact with certain medications, verify interactions)
⦁ Combination (B1, B6, B12) helps relieve neuropathic pain (B6 is toxic at 1000mg per day, must use less than 100-200mg per day)
⦁ B12 can reverse neuropathy and support clinical recovery (dose range 20-1840mcg cyanocobalamin or 4-1500mg methylcobalamin)
⦁ D Vitamins (D2, D3)
⦁ supplementation is only beneficial for deficiency. do not supplement long-term as it may cause toxicity
⦁ maintain calcium and magnesium levels
⦁ 1000-2000IU per day, more than 2000IU and blood levels should be monitored
⦁ D3 is preferred over D2
⦁ Magnesium
⦁ combination with B, C, E and Zinc (also omega 3s) help alleviate neuropathy
⦁ dose range 250-500mg start lower and increase
⦁ dose differs based on type (magnesium oxide, magnesium citrate, magnesium gluconate, etc.)
⦁ magnesium oxide has less absorption and bioavailability
⦁ magnesium citrate also used as a laxative
⦁ most common side effect is laxative due to nonabsorption, choose type that works for you
⦁ interacts with many medications, verify interactions
I am still selecting vitamin and mineral brands. Vitamin C + Zinc is an available formulation as well as a Calcium+Magnesium+Zinc+D3 formulation. I need to check formulation concentrations and compare the costs of buying a formulated mix to the cost of buying each supplement as a stand-alone.
I am also stopping my usual multivitamin to prevent possible overdose on any of the above listed supplements. I am creating a supplement regimen specifically to alleviate the neuropathy and withdrawal symptoms I am experiencing with the duloxetine taper. Once I have completely stopped duloxetine and my neuropathy has improved, I will return to my previous supplement regimen of a multivitamin and Omega 3. I use the Twice-Per-Day multivitamin by LifeExtension, it is the most potent and broad spectrum multivitamin I found containing recommended doses for the majority of vitamins and minerals, plus some super-food extract combinations.
When verifying potential drug interactions when using supplements, also check to see if there are any physiological interactions. Some supplements will decrease blood sugar which is a concern for diabetics, or decrease blood pressure, or have an anti-coagulant effect and increase the possibility of bleeding. Make sure to inform your doctor, and when having surgery, it is recommended to stop using most supplements for at least 2 weeks prior to the surgery. Also check supplements for compatibility, as some are powerful antioxidants, and if used with other antioxidants, the doses should be reduced.

[fishinghat]

Peripheral neuropathy (cont)

Sk8rmama24 - (update) - I ended up stopping everything that was non-essential and holding my duloxetine reduction plan because of some of the issues I was having. Still haven't figured out the cause of any of it though. Been to the urgent care and ER more times than I would like, and still nothing. I call the cardiologist tomorrow to get the results from the heart monitor I wore for a weekend. Now I have a referral to a neurologist though, last time I was in the ER they called it an atypical migraine that didn't respond to anything. Never knew a migraine could make your neck so stiff it wouldn't move, I was worried I had meningitis.

FH - A good deal of work there Sk8.

Some notes.

Omega 3 - Good info. There is also enteric coated Omega 3 to help avoid stomach upset.

Neurovascular -
B1 - Note - Use of thiamine supplements may increase gaba concentrations in the brain but it may also increase acetylcholine. This may account for the variety of responses by members.

B1 (thiamine) is the most active form is thiamine pyrophosphate (TPP), a coenzyme in the breakdown of sugars and amino acids. Synthetically thiamine is usually marketed as thiamin hydrochloride or thiamin mononitrate and is a made from Grewe diamine (a coal tar derivative) processed with ammonia and other chemicals.

Vitamin B1 toxicity is very rare but supplements can lower other vitamins.

B3 - The FDA does not recommend the taking of vitamin B3 supplements due to its toxic effects on the liver if taken over the RDA.

Taking niacin also might worsen allergies, gallbladder disease and symptoms of certain thyroid disorders. If you have diabetes, niacin can interfere with blood glucose control. Use niacin with caution if you have the complex form of arthritis gout. Niacin can cause an excess of uric acid in the blood (hyperuricemia), putting you at risk of gout. (Mayo Clinic)

B5 -Extremely high doses have been found to produce panic attacks. Synthetic pantothenic acid is processed with formaldehyde (a strong cancer causing agent. It exists in 2 other forms; pantotheno and calcium pantothenate.

B6 -The RDA is 1 – 3 mg/day. Doses of pyridoxine in excess of the RDA over long periods of time result in painful and ultimately irreversible neurological problems. There are 7 forms; Pyridoxine (most common), Pyridoxine 5'-phosphate, Pyridoxal, Pyridoxa 5'-phosphate, the metabolically active form (sold as 'P-5-P' vitamin supplement) Pyridoxamine (PM), Pyridoxamine 5'-phosphate (PMP) and 4-Pyridoxic acid (PA). Due to its half life of up to 25 days it is easy to buildup toxic amounts in the blood stream. Vitamin B6 toxicity is on the rise in the USA. The FDA recommends that supplementation does not exceed 3 mg per day with blood tests every 6 months.

[fishinghat]

Peripheral neuropathy (cont)

Vitamin B6 Toxicity

Note - A search of vitamin B6 supplements on Amazon shows that many supplements currently on the market are well above the recommended dietary allowances. The long half life (see below) allows for toxic levels to build rapidly.

Cin - a good mult-vitamin, but don't overdo it on the B vitamins (even though they are water soluble, I actually got vit. B6 toxicity and that caused some nerve issues that I'm not sure will ever completely reverese),

FH - My wife developed Vitamin B6 toxicity by taking a stress tab with 5 mg dose once a day for several years. The dr said it would take her 6 months to recover and that recovery may not be complete.

https://www.ncbi.nlm.../pubmed/6308447
We describe seven adults who had ataxia and severe sensory-nervous-system dysfunction after daily high-level pyridoxine (vitamin B6) consumption. Four were severely disabled; all improved after withdrawal. Weakness was not a feature of this condition, and the central nervous system was clinically spared. Although consumption of large doses of pyridoxine has gained wide public acceptance, this report indicates that it can cause sensory neuropathy or neuronopathy syndromes and that safe guidelines should be established for the use of this widely abused vitamin.

https://www.ncbi.nlm...ooks/NBK114313/
Half-Life is 15 to 24 days.
https://www.ncbi.nlm.../pubmed/3041185
Pyridoxine neuropathy.
A case of sensory neuropathy in a young woman due to long-term ingestion of pyridoxine, with subsequent recovery, is described. Pyridoxine neuropathy may occur after the long-term ingestion of doses as low as 200 mg a day. Because of its widespread use in the community, both the general public and the medical community need to be aware of this recently described complication of megavitamin therapy.
https://www.ncbi.nlm.../pubmed/3630649
A newly recognized neurotoxic syndrome due to pyridoxine (B6) overdose is described. It is the largest series of B6 intoxication hitherto reported. A raised serum B6 level was present in 172 women of whom 60% had neurological symptoms, which disappeared when B6 was withdrawn and reappeared in 4 cases when B6 was restarted. The mean dose of B6 in the 103 women with neurological symptoms was 117 +/- 92 mgs, compared with 116.2 +/- 66 mgs in the control group. There was a significant difference (P less than 0.01) in the average duration of ingestion of B6 in the neurotoxic group of 2.9 +/- 1.9 years compared with 1.6 +/- 2.1 years in controls. The symptoms were paraesthesia, hyperaesthesia, bone pains, muscle weakness, numbness and fasciculation, most marked on the extremities and predominantly bilateral unless there was a history of previous trauma to the limb. These women were taking a lower dose of B6 than previously described (1,2), which may account for the complete recovery within 6 months of stopping B6.
https://www.ncbi.nlm...pubmed/25056196

Vitamin B9 (folate) - Alcohol interferes with folate absorption. It also increases folate excretion through the urine.

D3 - May cause constipation, nausea and vomiting as these are symptoms of an allergic reaction that require immediate medical attention. If taking vit d3 you should have your calcium and D3 levels checked each 6 months. Long term use can cause hypercalcemia (too high calcium levels and low magnesium levels (hypomagnesaemia).

Vitamin C - Sensitivity to Vitamin C is fairly common with doses of 200 or more mg per day causing heart pounding, cardiac arrhythmias and flushing. Two of our members have experienced that condition.

Vitamin E - Supplementation may lower Vitamin K levels in the body which should be routinely monitored.

Magnesium - Supplementation can cause a decrease in calcium leading to hypocalcemia. Calcium and magnesium levels should be checked every 12 months if using supplements.

The most readily absorbed for is amino acid chelate magnesium. It is also very easy on the stomach and the risk of diarrhea is low.

Zinc -
Excess zinc...
⦁ Zinc may accumulate and cause acute kidney injury.
⦁ Those with haemochromatosis may absorb larger amounts of zinc.
⦁ Various pesticides contain zinc salts.
⦁ Compounds used to make paints, rubber and dyes may also contain zinc.
⦁ Zinc absorption from dandruff shampoos and denture creams. (numerous lawsuits pending)
⦁ Supplements, Increasing in occurrence.

⦁ People taking large amounts of iron supplementation (iron can interfere with zinc absorption).

Sk8rmama24 - "I will also include a recommendation that any supplement regimen that is being changed or started should be done so conservatively. I am not going to begin all supplements at once, that is never recommended, usually the approach is take 1 type of new supplement (no more than 2) at a time for a week or two, to determine potential side effects or issues that could arise. Plus many of the supplement doses I researched come with the recommendation to start with a low dose and increase over time, so this will be an involved process."

Brilliant idea. I follow what the old time drs called the "tea cup/teaspoon" method. Yes, I am that old. Basically it goes....If the dr prescribes that you take a teacup full just start with a teaspoon full and slowly work your way up. And as an scientist we were always taught in college never change two things at once. If something goes bad, or even improves, you won't know which one was responsible
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[fishinghat]

Adrenal Insufficiency
"Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones, primarily cortisol; but may also include impaired production of aldosterone (a mineralocorticoid), which regulates sodium conservation, potassium secretion, and water retention. Craving for salt or salty foods due to the urinary losses of sodium is common." - Wiki

First of all it is a condition not a disease. Just like a headache from a brain tumor would be considered a condition while the tumor would be considered the causative disease.

Symptoms ....

"Signs and symptoms include: hypoglycemia, dehydration, weight loss, and disorientation. Additional signs and symptoms include weakness, tiredness, dizziness, low blood pressure that falls further when standing (orthostatic hypotension), cardiovascular collapse muscle aches, nausea, vomiting, and diarrhea." Wiki
There are three major types of adrenal insufficiency.
⦁ Primary adrenal insufficiency is due to impairment of the adrenal glands.
⦁ 80% are due to an autoimmune disease called Addison's disease or autoimmune adrenalitis.
⦁ One subtype is called idiopathic, meaning of unknown cause.
⦁ Other cases are due to congenital adrenal hyperplasia or an adenoma (tumor) of the adrenal gland.
⦁ Secondary adrenal insufficiency is caused by impairment of the pituatary gland or hypothalamus. Its principal causes include pituatary adenoma and Sheehan's syndrome, which is associated with impairment of only the pituitary gland.
⦁ Tertiary adrenal insufficiency is due to hypothalmic disease and a decrease in the release of corticotropin releasing hormone (CRH). Causes can include brain tumors and sudden withdrawal from long-term exogenous steroid use (which is the most common cause overall).
There are a series of tests that can be run for this condition as well as pituitary or hypothalmis conditions.
I could find no medical research linking adrenal insufficiency to anxiety but found several linking it to depression.
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Adrenal Fatigue or hypoadrenia is a fictious condition believed in alternative medicine, to be the state when adrenal glands are exhausted and unable to produce adequate quantities of hormones, primarily the glucocorticoid cortisol, due to chronic stress or infections. Adrenal fatigue should not be confused with actual forms of adrenal dysfunction such as adrenal insufficiency or Addison's disease. - Wiki

http://www.cymbaltaw...tion#entry61576
Information on Dr. Tracy and adrenal fatique.
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[fishinghat]

Treatment Resistant Anxiety/Depression (Dysthemia).
https://www.ncbi.nlm...pubmed/27244871
Since SSRIs and other new antidepressant agents entered the market the possibilities to treat depression improved substantially but 25-35 percent of major depressives do not respond even to the second antidepressant trial but the rate of patients who are resistant after the third and fourth adequate antidepressant trial are around only 15-25 and 10 percent, respectively.

http://journal.front...2013.00146/full
Using these criteria, several studies, including the naturalistic STAR*D study, have shown that only one third of MDD patients receiving ADs achieve complete remission after a single AD trial. The remission rate reaches up to 60% after four trials, but the probability of remission drops significantly after the failure of two consecutive AD trials. Moreover, early improvement predicts sustained response and remission. Consequently, the concept of treatment-resistant depression (TRD) was proposed to describe depressive conditions that did not reach sufficient remission after treatment.

https://www.ncbi.nlm...pubmed/25439852
Treatment-resistant anxiety disorders: A literature review of drug therapy strategies.

https://www.ncbi.nlm...pubmed/25110830
Clinical effectiveness of interventions for treatment-resistant anxiety in older people: a systematic review.

https://www.ncbi.nlm...les/PMC4928674/
Anxiety disorders are highly prevalent mental disorders with the potential to be persistently disabling if not treated. Both psychotherapy and pharmacotherapy (PT) have demonstrated their treatment efficacy. Nevertheless, almost 30%–60% of patients continue to be symptomatic after outpatient management.

https://www.ncbi.nlm...pubmed/27175543
AUGMENTATION STRATEGIES FOR TREATMENT-RESISTANT ANXIETY DISORDERS: A SYSTEMATIC REVIEW AND META-ANALYSIS.

http://www.psychiatr...ic-perspectives
Although effective treatments are available, such as the SSRIs and cognitive-behavioral therapy (CBT), it is estimated that in about 40% of patients, anxiety disorders are partially or completely resistant to first-line treatment.1 The underlying causes of such high rates of treatment resistance are unclear, but these patients are likely to pose a major challenge for psychiatrists, since most first-line treatments are administered by nonpsychiatric physicians, whereas refractory anxiety disorders are the domain of psychiatrists.

http://www.psychiatr...article/385638/
According to a review of treatment-resistant anxiety published in the journal Molecular Psychiatry, only about 60% of patients with anxiety respond to front-line treatments. Up to 30% of patients may be treatment resistant.

FYI, In the new DSM-5, dysthymia is replaced by persistent depressive disorder (PDD).

https://www.ncbi.nlm...pubmed/21536001
These results support the utility of certain antidepressants (tricyclics, nefazodone) in treating depression in patients with comorbid alcohol use disorders. More data on the use of newer antidepressants, including the SSRIs, for this select patient population are needed.

https://www.ncbi.nlm...pubmed/21190638
Individuals with CMDD and dysthymic disorder share many sociodemographic correlates, comorbidity patterns, risk factors, and course. Individuals with chronic depressive disorders, especially those with dysthymic disorder, continue to face substantial unmet treatment needs.
Translation, hard to treat.

https://www.ncbi.nlm...pubmed/25177490
Duloxetine at relatively high doses showed moderate efficacy in elderly patients with dysthymic disorder
Not exactly a good choice for treatment.

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Treatment Resistant Anxiety/Depression (Dysthemia) (Cont)

https://www.ncbi.nlm...pubmed/21527126
This study states that antidepressants in geneneral are as effective or more effective against dysthymia than against major depressive disorder.

There are so many articles on the use of antidepressants to treat dysthymia. Some say one AD works and the next one says it doesn't. Articles specifically addressing dysthymia usually comment that AD use can be effective but is very hit and miss. They usually state that dysthymia patients go through trials of many medications before being successful. Here is a good one....

https://www.ncbi.nlm...pubmed/21154393
Second-generation antipsychotics for major depressive disorder and dysthymia.
"Quetiapine was more effective than placebo treatment. Aripiprazole and quetiapine and partly also olanzapine and risperidone augmentation showed beneficial effects compared to placebo. Some evidence indicated beneficial effects of low-dose amisulpride for dysthymic people. Most SGAs showed worse tolerability."
When they say "more effective than placebo" they are indicating an improvement but usually not substantial. And "Most SGAs showed worse tolerability." means the other treatments made the dysthymia worse.

https://www.ncbi.nlm...pubmed/23389382
Use of Cymbalta not effective for dysthymia.
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Blood Brain Barrier

Brain Areas Without a Blood Brain Barrier.
All areas of the brain do not have a blood-brain barrier. The structures located at strategic positions in the midline of the ventricular system and lack the BBB are collectively referred to as circumventricular organs (CVOs). In these non-barrier regions, the tight junctions between endothelial cells are discontinuous thus allowing entry of molecules.  Many of these areas participate in hormonal control.

Areas of brain without a blood-brain barrier:
Pituitary gland
http://www.ncbi.nlm..../pubmed/2571183
biogenic amines, including the catecholamines (norepinephrine, dopamine and epinephrine), serotonin, acetylcholine and gamma-aminobutyric acid (GABA).

Median eminence
http://www.ncbi.nlm....les/PMC2929984/

The median eminence is a very unusual neural structure: although it contains nerve terminals and glial cells, it is virtually devoid of synapses and it has structural properties that distinguish it from other brain regions. We provide information about the molecular, anatomical and physiological features of the median eminence, and their age-related changes. The hypothalamic system controlling reproduction through the release of the gonadotropin-releasing hormone (GnRH) peptide from nerve terminals in the median eminence. The hypothalamic-pituitary-gonadal (HPG) axis of females includes GnRH cells and terminals in hypothalamus; the pituitary gonadotropes which produce the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH); and the ovary, which produces steroid (particularly estradiol and progesterone) and protein hormones. All of the HPG levels must function normally for reproduction to occur, and during aging, each of these levels undergoes changes that may conribute to reproductive dysfunction and ultimately failure.

Area postrema
Chemoreception
The area postrema, one of the, circumventricular organs detects toxins in the blood and acts as a vomit-inducing center. The area postrema is a critical homeostatic integration center for humoral and neural signals. Recent studies have implicated its function as a chemoreceptor trigger site for vomiting in response to emetic drugs. It is a densely vascularized structure that lacks tight junctions between endothelial cells, thereby allowing it to detect various toxins in the blood as well as in the cerebrospinal fluid.

Autonomic Regulation
The area postrema position outside of the blood brain barrier makes this particular region of the medulla a key player in the autonomic control of various physiological systems, including the cardiovascular system and the systems controlling feeding and metabolism. A recent study has indicated the existence of prolactin-binding sites specific to the area postrema. The result of the current study has implicated the area postrema as a prolactin target area at which vascular prolactin has the ability to openly associate with neuronal components. Prolactin is a peptide hormone known in lower animals to play a significant role in osmoregulation, originally functioning to influence electrolyte balance, and may now be believed to stimulate reproductive behaviors such as the water-drive before ovoposition in amphibians and lactation in mammals. Another recent study found that the administration of angiotensin II causes a dose-dependent increase in the arterial blood pressure without producing considerable changes in the heart rate. Evidence from this study reveals that the change in the arterial blood pressure depends on the integrity of the area postrema and that this site partially contributes to the action of angiotensin.

Preoptic recess
Molecules like dopamine stimulate cells in this portion of the preoptic area, and when stimulated, these neurons regulate male sexual behavior. Animal studies have shown that stimulation results in copulation behavior and the release of compounds like gonadotropin-releasing hormone. Higher dopamine stimulation is seen in response to testosterone levels, as well as by sensory stimulation, such as the presence of a female.

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Blood Brain Barrier (cont)

Paraphysis

Pineal gland
The pineal gland, also known as the pineal body, conarium or epiphysis cerebri, is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of sleep patterns in the circadian rhythms and seasonal functions
Unlike much of the rest of the mammalian brain, the pineal gland is not isolated from the body by the bloodrain barrier system; it has profuse blood flow, second only to the kidney.

Endothelium of choroid plexus
The choroid plexus plays a wide range of roles in brain development, maturation, aging process, endocrine regulation, and pathogenesis of certain neurodegenerative diseases [1]. The choroid plexuses consist of a single layer of epithelial cells enclosing a vascular core that together form the blood-cerebrospinal fluid barrier [2]. The choroidal capillary is a single layer of endothelial cells interrupted by “pores” which exhibit a diaphragm between the lumen and the interstitial space. Study shows that choroid plexus endothelial cells express high Glut1 glucose transporter [3]. The high glucose transport densities in choroids plexus endothelial cells is consistent with the suggestion that choroids epithelial and endothelial cells provide a metabolic work capability for maintaining ionic gradients and secretory functions across the blood-cerebrospinal fluid barriers.

Neurotransmitter across BBB
http://www.jci.org/a...canned-page/145
Transport of hormones across BBB

http://www.ncbi.nlm....8?dopt=Abstract
Small amounts of glutamate cross bbb.

http://www.ncbi.nlm....1?dopt=Abstract
Small amounts of glutamate cross bbb.

http://www.ncbi.nlm....9?dopt=Abstract
Glutamate across bbb

http://www.ncbi.nlm....7?dopt=Abstract
Glutamate across bbb

http://ajpcell.physi...pe2=tf_ipsecsha
Glutamate across bbb

http://www.ncbi.nlm....les/PMC3001209/
Melatonin passes through bbb.

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Blood Brain Barrier (cont)

Common Neurotransmitters

Chem. Family Transmitter Name Does it cross BBB Reference
Small: Amino acids (Arg)Agmatine Yes http://www.ncbi.nlm....pubmed/15028571
Small: Aminoacids Aspartate Limited http://articles.merc...ain-health.aspx
Small: Amino acids Glutamate (glutamic acid) Limited to moderate See Notes
Small: Amino acids Gamma-aminobutyric acid No
Small: Amino acids Glycine Limited http://www.ncbi.nlm....books/NBK28180/
Small: Amino acids D- serine Limited http://www.sciencedi...197018612001027
Small: Acetylcholine Acetylcholine No http://the-medical-d...e_article_5.htm
Small: Monoamine (Phe/Tyr)Dopamine No
Small: Monoamine (Phe/Tyr)Norepinephrine (noradrenaline) Minimal http://www.ncbi.nlm....v/pubmed/961901
Small: Monoamine (Phe/Tyr)Epinephrine (adrenaline) No
Small: Monoamine (Trp)Serotonin (5-hydroxytryptamine) 1 – 2% if brain seratonin low.
http://www.life-enha...cts-and-fiction
Small: Monoamine (Trp)Melatonin Yes http://www.ncbi.nlm....les/PMC3001209/
Small: Trace amine (Phe)Phenethylamine Yes http://www.ncbi.nlm....v/pubmed/408734
Small: Trace amine (Phe)N-methylphenethylamine Unk
Small: Trace amine (Phe/Tyr)Tyramine No http://www.ncbi.nlm..../pubmed/6492942
Small: Trace amine (Phe/Tyr)Octopamine Unk
Small: Trace amine (Phe/Tyr)Synephrine Yes
http://www.ncbi.nlm....86/#!po=8.33333
Small: Trace amine (Phe/Tyr)3-methoxytyramine No
Small: Trace amine (Trp)Tryptamine Yes http://www.ncbi.nlm....pubmed/21628792
Small: Trace amine (Trp)Dimethyltryptamine Yes
Small: Diamine (His)Histamine Unk
NeuropeptidesN-Acetylaspartylglutamate Moderate Riveros, N.; Orrego, F. (1984). "A study of possible excitatory effects of N-acetylaspartylglutamate in different in vivo and in vitro brain preparations". Brain Research 299 (2): 393–395. doi:10.1016/0006-8993(84)90727-3. PMID 6145497.
PP: Gastrins Gastrin Unk
PP: Gastrins Cholecystokinin No http://en.wikipedia....Cholecystokinin
PP: Neurohypophyseals Vasopressin Yes http://www.ncbi.nlm..../pubmed/2364078
PP: Neurohypophyseals Oxytocin No http://psychcentral....xytocin/0001386
PP: Neurohypophyseals Neurophysin I Unk
PP: Neurohypophyseals Neurophysin II Unk
PP: Neuropeptide Y Neuropeptide Y Yes http://ajpendo.physi...tent/276/3/E479
PP: Neuropeptide Y Pancreatic polypeptide Yes http://www.sciencedi...09130579400412C
PP: Neuropeptide Y Peptide YY Moderate http://www.sciencedi...471489204001602
PP:OpioidsCorticotropin (adrenocorticotropic hormone) Yes http://www.researchg...d-brain_barrier
PP: Opioids Enkephaline Yes http://www.cs.columb...brain/text.html
PP: Opioids Dynorphin Yes http://www.sciencedi...196978112004202
PP: Opioids Endorphin Minimal http://en.wikipedia.org/wiki/Endorphin
PP: Secretins Secretin Yes http://www.ncbi.nlm....pubmed/15134484
PP: Secretins Motilin Unk
PP: Secretins Glucagon Unk
PP: Secretins Vasoactive intestinal peptide Yes http://www.sciencedi...196978103000597
PP: Secretins Growth hormone-releasing factor No http://www.ncbi.nlm....pubmed/10392357
PP: Somatostatins Somatostatin Yes http://www.ncbi.nlm....les/PMC1573221/
SS: Tachykinins Neurokinin A Unk
SS: Tachykinins Neurokinin B Unk
SS: Tachykinins Substance P Yes
http://www.ncbi.nlm....pubmed/16729222
PP: Other Bombesin Moderate http://www.sciencedi...19697819090064C
PP: Other Gastrin releasing peptide No
http://www.sciencedi...006899304017974
Other Anandamide Yes http://addiction-dir...-marijuana.html
Other 2-Arachidonoylglycerol Unk
Other 2-Arachidonyl glyceryl ether Yes http://www.northeast...arch/index.html
Other ''N''-Arachidonoyl dopamine poor http://www.sciencedi...471489202000061
Other Virodhamine Unk
Other Adenosine triphosphate Some http://davislab.med....ain-barrier-bbb
Other Adenosine Yes http://jpet.aspetjou...ontent/268/1/14
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Brain Zaps
http://www.ncbi.nlm....les/PMC3733524/
http://www.ncbi.nlm....489/pdf/405.pdf
pg 408

http://www.bmj.com/c...nt/331/7520/824
http://pb.rcpsych.org/content/29/6/219
These are things that previous members have ewported good success with in controling brain zaps.
Dramamine, Meclizine, Rugby Travel Med (Meclizine plus phenylalanine)
The Rugby travel med is probably your best bet.
Also, have you had your blood sugar checked recently? Low blood sugar can lead to this condition.
I checked the medical journals and there is no mention of a treatment for this, only that it is a symptom of many withdrawals.
I did find this one medical journal article that mentioned that "brain shiver" (another name for brain zaps) has been treated with Atomoxetine.
https://www.ncbi.nlm...les/PMC3733524/
A Case of Amelioration of Venlafaxine-Discontinuation “Brain Shivers” With Atomoxetine
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Genetics
Anxiety and Depression Genes
https://www.ncbi.nlm...pubmed/25801102
Optimizing treatments for anxiety by age and genetics.
Abstract
This paper highlights recent human neuroimaging and cross-species developmental and genetic studies that examine how fear regulation varies by age and the individual, especially during the period of adolescence, when there is a peak in the prevalence of anxiety disorders. The findings have significant implications for understanding who may be at risk for anxiety disorders and for whom, and when, an exposure-based therapy may be most effective. We provide proof of concept for targeting treatment to the individual as a function of age and genetics, inferred from mouse and human studies, and suggest optimization of treatment for nonresponders.

https://www.ncbi.nlm...pubmed/25106036
Are there depression and anxiety genetic markers and mutations? A systematic review.

https://www.ncbi.nlm...pubmed/24390875
https://www.ncbi.nlm...pubmed/25350786
https://www.ncbi.nlm...pubmed/25262417
https://www.ncbi.nlm...pubmed/25251027
https://www.ncbi.nlm...pubmed/25547397
https://www.ncbi.nlm...pubmed/23986266
https://www.ncbi.nlm...pubmed/25249351


http://www.webmd.com...ponse-to-stress
Summarizes research on a depression gene.

http://www.psycholog...-disorder-fkbp5
Anxiety Gene

http://www.ncbi.nlm....les/PMC3181835/
Research on a anxiety gene.

http://www.livestron...ession-anxiety/
Genes as a factor for anxiety & depression.

http://www.ncbi.nlm....pubmed/23627963
Emotional Gene study on 4 year old children.


http://www.ncbi.nlm....les/PMC3285424/
Genetic Testing in Psychiatry: A Review of Attitudes and Beliefs

https://www.psycholo...ssion-treatment

http://onlinelibrary....20251/abstract
Genetic screening for SSRI drug response among those with major depression: great promise and unseen perils

http://www.psychiatr...iatric-practice
Genetic Testing for Psychiatric Disorders: Its Current Role in Clinical Psychiatric Practice

This is all the treatment details I could find but I can't say I feel warm and fuzzy about these results. Just not enough known yet.
SLC6A4 in the L(A)/S form
This form cause depression and depression.
Patients (especially of european descent) tend not to respond to ssri and as such treatment is more likely to succeed if a non-ssri AD is used.
BDNF Val/Met gene
A cause of bipolar disorder.
Lithium and valproate (Depakote) responses better in Val/Met gene than other BDNF genes.
This gene morph did not alter the effectiveness rate of Effexor.
This gene type usually predicts that antipsychotics are ineffective.
COMT Met/Met gene
Individuals With COMT Variant Show Exaggerated Reaction to Aversive Stimuli
venlafaxine (Effexor)and lamotrigine ( Lamictal) have been used successfully to treat this condition.
By itself Effexor has limited effectiveness.
This gene may lead to ADHD and can usually be treated with low dose amphetamines but usually suffer adverse reactions.
Creates higher amounts of dopamine in the frontal cortex.
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Phantosmia
[Phantosmia (phantom smell), also called an olfactory hallucination, is smelling an odor that is not actually there.]

https://www.ncbi.nlm...pubmed/24122320
Olfactory cocainization is not an effective long-term treatment for phantosmia.
Phantosmia, the perception of an odor when there are no odorants in the environment, can be a very debilitating symptom. In the 1960s, Zilstorff reported olfactory distortions could be treated by the topical application of a cocaine solution to the olfactory epithelium. In evaluating this treatment, we observed no long-term benefit using cocaine on 6 patients with phantosmia. Based on our observations, the patient's olfactory ability was not a determining factor in the initiation or quality of their phantosmia. Following topical cocainization, we observed a remarkable delay of hours to days in the return of olfactory ability, and when cocaine was applied to only 1 nostril, there was a decreased olfactory ability on the noncocainized side. These results may suggest the possibility that phantosmia is related to a central processing problem.

https://www.ncbi.nlm...pubmed/23883685
http://search.proque...igsite=gscholar
Enhanced parosmia and phantosmia in patients with severe depression.
Note - Parosmia, also known as troposmia (Gk.) or cacosmia, (Gk.) is an olfactory dysfunction that is characterized by the inability of the brain to properly identify an odor's "natural" smell. What happens instead, is that the natural odor is transcribed into what is most often described as an unpleasant aroma, typically a "'burned,' 'rotting,' 'fecal,' or 'chemical' smell."

https://www.ncbi.nlm...pubmed/23456373
Phantosmia as a meteorological forecaster.
In normosmics, olfactory ability has been found to vary with ambient humidity, barometric pressure, and season. While hallucinated sensations of phantom pain associated with changes in weather have been described, a linkage to chemosensory hallucinations has heretofore not been reported. A 64-year-old white male with Parkinson's disease presents with 5 years of phantosmia of a smoky burnt wood which changed to onion-gas and then to a noxious skunk-onion excrement odor. Absent upon waking it increases over the day and persists for hours. When severe, there appears a phantom taste with the same qualities as the odor. It is exacerbated by factors that manipulate intranasal pressure, such as coughing. When eating or sniffing, the actual flavors replace the phantosmia. Since onset, he noted the intensity and frequency of the phantosmia forecasted the weather. Two to 3 h before a storm, the phantosmia intensifies from a level 0 to a 7-10, which persists through the entire thunderstorm. Twenty years prior, he reported the ability to forecast the weather, based on pain in a torn meniscus, which vanished after surgical repair. Extensive olfactory testing demonstrates underlying hyposmia. Possible mechanisms for such chemosensory-meteorological linkage includes: air pressure induced synesthesia, disinhibition of spontaneous olfactory discharge, exacerbation of ectopic discharge, affect mediated somatic sensory amplification, and misattribution error with expectation and recall bias. This is the first reported case of weather-induced exacerbation of phantosmia. Further investigation of the connection between chemosensory complaints and ambient weather is warranted.

https://www.ncbi.nlm...les/PMC4061890/
Olfactory Hallucinations without Clinical Motor Activity: A Comparison of Unirhinal with Birhinal Phantosmia
Olfactory hallucinations without subsequent myoclonic activity have not been well characterized or understood. Herein we describe, in a retrospective study, two major forms of olfactory hallucinations labeled phantosmias: one, unirhinal, the other, birhinal. To describe these disorders we performed several procedures to elucidate similarities and differences between these processes. From 1272, patients evaluated for taste and smell dysfunction at The Taste and Smell Clinic, Washington, DC with clinical history, neurological and otolaryngological examinations, evaluations of taste and smell function, EEG and neuroradiological studies 40 exhibited cyclic unirhinal phantosmia (CUP) usually without hyposmia whereas 88 exhibited non-cyclic birhinal phantosmia with associated symptomology (BPAS) with hyposmia. Patients with CUP developed phantosmia spontaneously or after laughing, coughing or shouting initially with spontaneous inhibition and subsequently with Valsalva maneuvers, sleep or nasal water inhalation; they had frequent EEG changes usually ipsilateral sharp waves. Patients with BPAS developed phantosmia secondary to several clinical events usually after hyposmia onset with few EEG changes; their phantosmia could not be initiated or inhibited by any physiological maneuver. CUP is uncommonly encountered and represents a newly defined clinical syndrome. BPAS is commonly encountered, has been observed previously but has not been clearly defined. Mechanisms responsible for phantosmia in each group were related to decreased gamma-aminobutyric acid (GABA) activity in specific brain regions. Treatment which activated brain GABA inhibited phantosmia in both groups.
Note - Hyposmia is a reduced ability to smell and to detect odors.
No wonder that phantosmia has been linked to withdrawal considering the association with changes in GABA (neurotransmitter) activity.

https://www.ncbi.nlm...pubmed/21942993
Long lasting phantosmia treated with venlafaxine.
Qualitative olfactory disorders such as parosmia and phantosmia are not well investigated. In particular, the causes and treatment options for phantosmia are largely unknown. We report a case of long lasting phantosmia that disappeared under anti-depressive treatment, raising the question to what extent certain forms of qualitative olfactory disorders are an early symptom of depression.
Note - Venlafaxine does have a stabilizing effect on Gaba. See...
https://www.ncbi.nlm...pubmed/16075286
https://www.ncbi.nlm...pubmed/9453456/
https://www.ncbi.nlm...ubmed/12488792/
Et al.

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Phantosmia (Cont)

https://www.ncbi.nlm...pubmed/20714205
Idiopathic phantosmia: outcome and clinical significance.
RESULTS:
None of the patients had developed any severe health condition or Parkinson's disease. More than 5 years after the occurrence of phantosmia, more than 50% of the patients experienced disappearance (31.8%) or improvement (25%). In the remaining cases, phantosmia did not change (38.7%) or became worse (<5%).
CONCLUSION:
The main findings of the present study were that idiopathic phantosmia improves or disappears in almost two thirds of the patients after more than 5 years, and that idiopathic phantosmia seems to be more likely a harmless symptom rather than a reliable predictor of early Parkinson's disease or other severe diseases.
Note - idiopathic - The cause may not be readily apparent or characterized. In these cases, the origin of the condition is said to be idiopathic.

https://www.ncbi.nlm...pubmed/18779429
Phantosmias and Parkinson disease.
We propose phantosmia as a new premotor manifestation of PD (Parkenson's Desease) and suggest that qualitative abnormalities of olfaction, rather than the typical smell loss demonstrated in this condition, should be more carefully examined in the prodromal phase of PD.

https://www.ncbi.nlm...pubmed/17006637
A study on the prognostic significance of qualitative olfactory dysfunction.
We investigated the frequency and prognostic significance of qualitative olfactory dysfunction (parosmia, phantosmia) in a retrospective patient based study. A total of 392 patients with impairment of olfaction were tested at least two times for their olfactory function using the "Sniffin' Sticks". The mean interval between the first and the last test was 11 months. At the first visit 34% of all patients reported parosmia. Parosmia was most frequent in patients with postinfectious olfactory loss (56%), and less frequent in idiopathic, posttraumatic, sinunasal disease with frequencies of 10, 14, and 28%, respectively. In contrast, only 12% of all patients had phantosmias, with no significant differences between the patient groups. Improvement of olfactory function was found in 23% of all patients (n = 90). Pre-existing parosmia or phantosmia had no significant effect on recovery rate. Regarding qualitative olfactory dysfunction, 29% of those patients reporting parosmia reported relief of this symptom after an average of 12 months, whereas 53% of phantosmic patients lost phantosmia during the observation period. Although it has been suggested that olfactory distortion s could be regarded as an indicator of early recovery of decreased olfactory sensitivity, the current data indicate that occurrence of parosmia or phantosmia has little prognostic value. Phantosmia disappears at a faster rate than parosmia. These insights into qualitative olfactory dysfunction are regarded to be significant in the counseling of patients with olfactory loss.

https://www.ncbi.nlm...pubmed/16308262
Euosmia: a rare form of parosmia.
The nature of qualitative olfactory disorders such as phantosmia and parosmia is a matter of debate. Parosmia and phantosmia mainly occur in combination with post-traumatic or post-infectious olfactory loss. Rare causes of these disorders such as brain tumors, side-effects of drugs, paraneoplastic syndromes, psychiatric disorders or intracerebral haemorrhage have been reported. Parosmias are distorted sensations of smell elicited by an odor, whereas phantosmias persist permanently or occur without the presence of an odor source. Phantosmias differ widely in terms of their nature. In contrast, parosmias always seem to be unpleasant. We report the case of a female with post-infectious hyposmia who reported a pleasant parosmia to selected odorants. We have called this rare clinical presentation euosmia.

https://www.ncbi.nlm...pubmed/12049557
Long-term follow-up of surgically treated phantosmia.
Surgical excision of olfactory epithelium is an effective and safe method to relieve phantosmia while potentially preserving olfactory ability. The abnormal histological features of the excised olfactory tissue suggest at least some pathological condition in the peripheral olfactory system. This nasal surgery requires intensive olfactory evaluation and follow-up. It is also extremely difficult with significant risks, and therefore should be limited to specialized centers.

https://www.ncbi.nlm...pubmed/10966179
Physiologically initiated and inhibited phantosmia: cyclic unirhinal, episodic, recurrent phantosmia revealed by brain fMRI.
1) Unirhinal phantosmia can be demonstrated by brain fMRI as can birhinal phantosmia; 2) unirhinal phantosmia can be initiated and inhibited by physiological maneuvers reflected by changes in fMRI brain activation; 3) fMRI brain activation of unirhinal phantosmia is bihemispheric and independent of peripheral side of phantosmia or patient handedness; 4) anterior frontal brain region plays a significant role in both phantosmia initiation and inhibition as, to some extent, do temporal brain regions; 5) activation of brain GABAergic systems appears to play a role in inhibition of unirhinal phantosmia; and 6) unirhinal phantosmia, similar to birhinal phantosmia, may reflect a type of maladaptive brain plasticity similar to that hypothesized to be responsible for phantom limb pain.

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Phantosmia (Cont)

https://www.ncbi.nlm...pubmed/10667670
Taste and smell phantoms revealed by brain functional MRI (fMRI).
These results demonstrate that (a) phantom taste and smell can be revealed by fMRI brain activation, ( brain activation in response to taste and smell phantoms is localized in sensory-specific brain regions for taste and smell, respectively, © brain activation in response to memory of each phantom initiated the greatest degree of activation we had previously measured, and (d) treatment with thioridazine or haloperidol inhibited both the presence of each phantom and its associated fMRI brain activation. This is the first study in which phantom tastes and smells have been demonstrated by an objective technique and treatment that inhibited the phantoms was characterized by objective inhibition of fMRI activation. These two patients represent a relatively common group that may be classified as having primary phantageusia and phantosmia distinct from those with phantoms or auras secondary to neurological, migrainous, psychiatric, or other causes.

https://www.ncbi.nlm.../pubmed/1845270
Successful treatment of phantosmia with preservation of olfaction.
A 26-year-old woman had an 8-year history of phantosmia in her left nostril. The phantosmia could be eliminated by nostril occlusion or cocainization of the olfactory epithelium on the involved side. Because her symptoms and testing suggested a peripheral problem, a full-thickness "plug" of olfactory epithelium from under the cribriform plate (including all the fila olfactoria) was excised. At 5 weeks postoperatively, the phantosmia was completely gone, and her olfactory ability had returned to preoperative levels. Either the removal of abnormal peripheral olfactory neurons from the nose or the interruption of incoming signals to the olfactory bulb eliminated the phantosmia. This form of therapy for phantosmia offers an alternative to more radical procedures such as olfactory bulbectomy and may offer a significant sparing of olfactory ability.

https://www.ncbi.nlm...les/PMC3201003/
Re-establishment of olfactory and taste functions
Treatments -
Topical Steroids - Two open studies documented a significant improvement of olfactory performance after betamethasone drops or flunisolide drops administered by the so-called "head down forward technique" (see Figure 3 ). However, Heilmann et al. did not find any significant improvement after administration of topical steroids.
Oral steroids are often effective in cases that do not respond to topical steroids. Their specific mechanism of action on olfactory performance remains unclear, but effects via glucocorticoid receptors in the olfactory mucosa, or via regulation of adenosine triphosphate (ATP) activity in the olfactory mucosa are being discussed. So far, no placebo-controlled, double-blind studies have been performed.
Most cases of phantosmia are related to nasal or respiratory infections. These usually respond well to antibiotic treatment.
Olfactory Cleft Surgery - In certain cases with pathological findings confined to the olfactory cleft, lateralization of the middle turbinate may be of benefit, although conclusive data are still missing.
Postviral Olfactory Disorders - Every acute infection of the upper respiratory tract may potentially lead to an olfactory disorder, but the exact pathogenesis remains unclear. Elderly subjects and women are affected more often, and parosmia as well as dysosmia are common. Akerlund et al. observed an elevated olfactory threshold correlating with nasal congestion in 9 volunteers experimentally infected with coronavirus with subsequent development of a common cold. In 36 volunteers suffering from a common cold, reduced amplitudes of the initial components in olfactory potentials were seen in addition to elevated thresholds, even after use of the nasal decongestant oxymetazoline. This finding indicates that olfactory impairment may, in part, be independent of nasal congestion, thus explaining the failure of oxymetazoline to improve olfaction.
Biopsies usually reveal a patchwork pattern, i.e., olfactory and respiratory epithelia alternate, and the number of olfactory receptor neurons is reduced. It remains controversial whether the extent of damage observed correlates with olfactory dysfunction. Dendrites of the olfactory receptor neurons often have cytoplasmic inclusions whose function is not yet understood.
Treatment of Postviral Olfactory Disorders
Treatment with alpha-lipoid acid seems promising. In an open, prospective study, patients [n=23, 19 hyposmic patients, 4 functionally anosmic patients, based on "Sniffin' Sticks" test results, received alpha-lipoid acid (600 mg/day) for 4.5 months on average. Six patients experienced mild improvement and 8 patients clear improvement of olfactory performance. However, the authors stated that confirmation of these findings warrants a double-blind study because spontaneous recovery and regeneration are common in postviral olfactory disorders and may occur up to 2 years after viral exposure.
Treatment of Parosmia / Phantosmia
Apart from various drugs, e.g., antiepileptics, antidepressants, and local anesthetics , surgical removal of the olfactory epithelium, reported for the first time in 1991 by Leopold et al., may be of use. Long-term follow-up (for 5 years after surgery) revealed that 7 of 8 patients were completely free of complaints, with only 2 patients showing reduced olfactory performance. Bulbectomy may also be of use in specific cases.
Toxic Olfactory Disorders
Many substances, such as metals (e.g., lead or cadmium), organic substances (e.g., solvents or formaldehyde), inorganic substances (e.g., chlorine, CO, ammonium chloride), and other substances (e.g., cement dust) may be olfactotoxic. Although the olfactory epithelium is located away from the main airway, 10% to 15% of the inhaled air reaches the olfactory epithelium even without sniffing, thus causing exposure to potentially toxic substances. Chronic exposure is more likely to induce lasting damage than acute exposure.
Treatment of Toxic Olfactory Disorders
No treatments with proven success exist, and larger studies documenting a clear relationship between exposure and olfactory loss are missing. Nevertheless, careful assessment of the work-place history is essential for all olfactory disorders.

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Phantosmia (Cont)

Experimental Drugs and Other Treatments
Hormonal Therapy
Studies by Deems et al. showing that only a small percentage of postmenopausal women with olfactory disorders receive hormonal therapy triggered speculation about a protective effect of hormones. The smaller bulb volume in men suffering from post-traumatic olfactory disorders, relative to that in women, as well as olfactory performance in schizophrenic women shown to differ in relation to their menopausal status was interpreted along the same lines. In animal experiments, ovarectomized mice exposed to olfactotoxic substances recovered more quickly if they received hormonal replacement than did those not receiving any hormones. However, a longitudinal study in 62 women failed to confirm these findings; the only finding was a correlation between loss of olfaction and age progression.
Dopamine
Although it is established that the neurotransmitter dopamine is present in the olfactory bulb, existence of D2 receptors in the olfactory epithelium has only recently been described. Dopamine triggers neuronal differentiation and maturation in the epithelium in vitro, while on stimulation of the lamina propria, dopamine induces the liberation of substances that block neuronal differentiation. Dopamine led to a significantly reduced rate of apoptosis in olfactory biopsies of schizophrenic patients but clearly accelerated apoptosis in the olfactory epithelium of control subjects. In Parkinson's patients, Huisman et al. determined a doubling of dopaminergic cells in the olfactory bulb and interpreted this as a possible cause of the olfactory disorders seen in Parkinson's disease.
Acupuncture
Data confirming the benefit of acupuncture are missing. In an open study, auricular acupuncture improved olfactory threshold in 23 healthy volunteers. In addition, a case report documented restored olfaction after acupuncture in a female patient who had been suffering from anosmia for 2 years.
Theophylline
Levy et al. used theophylline (250 to 500 mg, given for 4 to 6 months) in 4 hyposmic patients (allergic rhinitis, n=3; post-traumatic hyposmia, n=1) and reported normal post-treatment olfaction in 2 patients, improved olfaction in 1 patient, and unchanged olfaction in the remaining patient. Functional MRI in 3 patients indicated enhanced central activation after treatment. No additional data are available.
Growth Factors (Transforming Growth Factor)
Olfactory receptor neurons are continuously replaced during the course of life, with the rate highest at younger age. Because the rate of neurogenesis can be manipulated by external factors (e.g., doubling after ablation of one olfactory bulb, decrease after unilateral nostril occlusion), acceleration by using growth hormones appears feasible. Intraperitoneal administration of transforming growth factor-alpha (TGA-alpha) resulted in enhanced cell proliferation not only in fetal but also in adult mice. So far, no studies in humans have been performed.
Vitamin A
Vitamin A has been reported to normalize olfactory performance in malabsorption conditions or A-β-lipoproteinemia. Moreover, Garrett-Laster et al. reported a significant improvement of olfactory threshold for pyridine and taste threshold for bitter and salty substances in 37 patients with vitamin A deficiency due to alcoholic liver cirrhosis undergoing a 4-week therapy with oral vitamin A (10 mg/day). No additional data are available.
Zinc
Zinc sulfate (100 mg) did not have any significant effects in 106 patients participating in a double-blind study reported by Henkin et al. (see also Quint et al.). High doses of local intranasal zinc may even be olfactotoxic.

https://www.ncbi.nlm...les/PMC3450842/
Olfaction — Quantification and management
Neuroimaging: Presently, high resolution CT appears to be the most useful and cost-effective screening tool for the assessment of sinunasal tract inflammatory,disorders. The nasal cavity, paranasal sinuses, hard palate, anterior skull base, orbits and nasopharynx should be scanned and if central causes of olfactory dysfunction are suspected, the brain as well.

MRI is the modality of choice for evaluation of the olfactory bulbs, olfactory tracts and intracranial causes of olfactory dysfunction because they can be visualized rather clearly on the coronal slices. Moreover MRI is the procedure of choice for evaluation if skull base invasion by sinunasal tumors is suspected. Gadolinium enhancement is particularly valuable for leptomeningeal involvement at the skull base. Its utility isin distinguishing solid enhancing tumors from rimenhancing inflammatory processes

Fluid and Tissue analysis: A complete blood count isessential to rule out infective, nutritional or hemopoetic processes if involved in smell dysfunction. A nonspecific
indication of autoimmune or inflammatory processes can be obtained from erythrocyte sedimentation rate. Since vitamin B 1 deficiency is clearly implicated in Wernicke-
Korsakoff syndrome, determination of erythrocyte thiamine level is indicated in patients with a significant history of suspected or documented chronic alcohol abuse.

Mucosat biopsies: For documentation of cellular changes at neuroepithelium, biopsies are, on rare occasion, performed by an experienced surgeon. In such cases a small piece of olfactory mucosa is stripped along the nasal septum by an endoscopic approach (Lovell et al 1982, Lanza et al 1993). The surgeon should perform multiple biopsies to obtain a reasonable accurate assessment of epithelial changes, given the considerable metaplasia of respiratory like epithelium in the region of olfactory neuroepithelium.

http://archotol.jama...rticleid=620253
Successful Treatment of Phantosmia With Preservation of Olfaction
A 26-year-old woman had an 8-year history of phantosmia in her left nostril. The phantosmia could be eliminated by nostril occlusion or cocainization of the olfactory epithelium on the involved side. Because her symptoms and testing suggested a peripheral problem, a full-thickness "plug" of olfactory epithelium from under the cribriform plate (including all the fila olfactoria) was excised. At 5 weeks postoperatively, the phantosmia was completely gone, and her olfactory ability had returned to preoperative levels. Either the removal of abnormal peripheral olfactory neurons from the nose or the interruption of incoming signals to the olfactory bulb eliminated the phantosmia. This form of therapy for phantosmia offers an alternative to more radical procedures such as olfactory bulbectomy and may offer a significant sparing of olfactory ability.

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Phantosmia (Cont)

http://www.academia...._Cell_Carcinoma
A Rare Cause of Phantosmia: Metastatic Small Cell Carcinoma
Olfactory hallucinations, known as phantosmias, are a poorly understood phenom-enon. It has been associated with a wide rage of differential diagnosis. However, most cases are idiopathic. The author’s presents a 70-year-old man with olfactory hallucinations as the predominant symptom of the brain metastatic small cell carcinoma in order to clarify the causal relationship. Little is known about the origin and clinical significance of phantosmias. It can even be the predominant symptom of an underlying small cell metastatic brain tumor as presented in our case. Therefore a detailed history of the symptoms along with a neurological and physical examination and routine laboratory and screening tests should be provided in order to exclude any organic causes.

http://microship.com...ation-syndrome/
Phantosmia and SSRI Discontinuation Syndrome A frustrating change of perception
My friend approached the problem with care, sticking to a schedule of tapering (Effexor) over four weeks, then at last took her final fraction of the prescribed dose. A nightmare immediately ensued, with intense anxiety, pain, and the classic “flu-like symptoms,” but she persevered and managed to keep her dosage level at zero. (It should be noted that some people take as much as 2 years to taper off this drug, so that may have been dangerously rapid.
Her acute discontinuation symptoms subsided after a few days… with one exception. Her sense of smell was broken.
In addition, she began to experience a disturbing phenomenon known as phantosmia, or the sensation of strong smells that don’t exist… usually smoke or “burning electrical cucumber.” At the same time, a prized fragrant rose smelled like cardboard.
Researching this, I began to find an unexpected connection… Effexor is often used to treat phantosmia. It is suspected that there is a link between mild depression and the detection of non-existent odors, a theory that has gained additional traction from the improvement of phantosmia after repeated transcranial stimulation used to treat depression. If this is indeed the case, we may be seeing a rebound effect similar to what happens when you stop taking a medication, with the original problem returning in stronger form. (When repeated, this is known as the kindling effect, where each withdrawal leads to an increasingly severe return of symptoms.)
GABA and Olfactory Attention
But why would our patient be experiencing this in the first place? What is the connection, if any, between the SNRI discontinuation and a mix of phantosmia and partial anosmia?
The conclusion of this paper is a provocative link that may be our culprit.
There has been research linking phantosmia with a depressed level of the inhibitory GABA in the CNS. In addition, there have been unrelated research
projects linking SSRI/SNRI discontinuation with disinhibition of the excitatory glutamatergic system. Discussion of this can get lost in double-negatives, but in essence, from the perspective of many parts of the brain, GABA is a brake and glutamine is an accelerator (a grotesque simplification, but instructive).
In one test, patients with phantosmia were seen to have reduced CNS GABA levels in the
cingulate, right and left insula, and left amygdala. This is particularly interesting, as a retrograde projection from the anterior cingulate cortex to the anterior olfactory nucleus appears to have a role in attention to olfaction… which reinforces our “automatic gain control”theory.
People often think of the antidepressant withdrawal syndrome as just being a matter of getting neurotransmitters back in balance, but it is more complex than that. The drugs damage an autonomic system, downregulating receptors (reducing their number), and thus removing some of the tools used to maintain
homeostasis. Discontinuation of the drug introduces CNS instability that manifests itself throughout the system… hence the extremely wide range of reported effects that include intense “brain zaps” and my own long-term crosstalk between lateral eye movement and somatosensory perception in the hands caused by a whiff of Remeron many years ago (6 half-doses, prescribed off-label for sleep). There is an enduring mythology that it is just
simple imbalance, but instead we are dealing with a dynamic self-correcting system… and there is ample evidence that this class of drugs causes actual damage from which recovery can be excruciatingly slow.
It would be interesting to do a test with GABAergic drugs (or receptor agonists) and attempt to recreate a phantosmia episode… that may confirm part of our theory, though not necessarily point to a useful solution.
The hopeful note in our patient’s case is that she reports a gradual improvement as the years pass. I believe she is being analytical about this and not just expressing adaptation to a static condition.

http://europepmc.org...ct/med/20022663
Improvement in smell and taste dysfunction after repetitive transcranial magnetic stimulation.
These results suggest that rTMS is a potential future therapeutic option to treat patients with the relatively common problems of persistent phantosmia and phantageusia with accompanying loss of taste and smell acuity. Additional systematic studies are necessary to confirm these results.

http://health.uconn....rticle_mann.pdf
Management of smell and taste problems

Drugs that can cause impaired smell or taste

Antidepressants and anticonvulsants
Amitriptyline, carbamazepine, clomipramine, clozapine, desipramine, doxepin, fluoxetine, imipramine, lithium, phenytoin, trifluoperazine

Antihistamines and cold medications
Chlorpheniramine, loratadine, pseudoephedrine, terfenadine

Antihypertensives and cardiac medications
Acetazolamide, adenosine, amiloride, benazepril and hydrochlorothiazide, betaxolol, captopril, clonidine, diltiazem, enalapril, ethacrynic acid, nifedipine, propranolol, spironolactone

Anti-inflammatories
Auranofin, colchicine, dexamethasone, diclofenac, dimethyl sulfoxide, gold, hydrocortisone, d-penicillamine,penicillamine

Antimicrobials
Ampicillin, ciprofloxacin, clarithromycin, ofloxacin, streptomycin, tetracyclines

Antineoplastics
Cisplatin, doxorubicin, methotrexate, vincristine

Bronchodilators and other asthma medications
Albuterol, cromolyn sodium, flunisolide, metaproterenol, terbutaline

Lipid-lowering drugs
Cholestyramine, clofibrate, fluvastatin, gemfibrozil, lovastatin, pravastatin

Muscle relaxants and drugs for parkinsonism
Baclofen, dantrolene, levodopa

Radiation therapy
Radiation of the head

Vasodilators
Dipyridamole, nitroglycerin patch

TREATMENT OF IMPAIRED SMELL

Drugs
Topical corticosteroids. In patients with anosmia due to edema from rhinosinusitis or
polyps, topical corticosteroids can bring striking improvement. Their lack of significant
adverse effects with long-term use is impressive compared with systemic corticosteroids.

Antibiotics, decongestants, antihistamines.
In patients with loss of smell due to bacterial infection, antibiotics (a penicillin or
cephalosporin), decongestants, and antihistamines are useful.Desensitization with the aid of an allergist is sometimes indicated if the smell problem isdue to allergic rhinitis.

Surgery
When conservative approaches are not sufficient, endoscopic nasal and sinus surgery can
produce dramatic changes.

Reassuring the patient
In patients with loss of smell following an upper respiratory tract viral infection, no
effective therapy is available. However, since olfactory cells may regenerate with time, from
months to years,20,21 patients can be told that their condition may eventually resolve.
Although not all patients can be helped, they deeply appreciate the attention andinvestigation given to them, because their previous visits to other physicians may have been frustrating.


https://www.utmb.edu...y-2003-1126.pdf
Olfactory Dysfunction and Disorders

Studies have shown that olfactory dysfunction affects at least 1 % of the population
under the age of 65 years, and well over 50% of the population older than 65 years.

https://www.aan.com/...e and Smell.pdf
TASTE AND SMELL DISORDERS IN CLINICAL NEUROLOGY
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SSRIs and Vision

https://www.ncbi.nlm...pubmed/11453869
Patients started on sertraline should be informed of the potential risk of developing maculopathy, and they should be examined regularly to detect possible early alterations.
Macular lesions resolved 6 months after discontinuation of sertraline.

https://www.ncbi.nlm...pubmed/10608673
She had taken Zoloft for 4 years and began a high-protein diet with melatonin supplementation 2 weeks before onset of visual symptoms. Visual acuity and color vision improved within 2 months after melatonin and the high-protein diet were discontinued. Combined use of melatonin, Zoloft, and a high-protein diet may have resulted in melatonin/dopamine imbalance in the retina, manifesting as a toxic optic neuropathy. Physicians and patients should be alerted to this potential drug interaction.

https://www.ncbi.nlm...pubmed/26139049
Clinical assessment and investigation confirmed ON (optic neuropathy) in all cases with a vascular origin suspected. SSRI cessation may help protect the unaffected eye and in some cases recovery of vision seems possible. The Naranjo scores indicated possible ADR (adverse drug reaction) in four cases and probable ADR in one case.

https://www.ncbi.nlm...pubmed/20443647
Thus, typical antipsychotics, TCAs, lithium, benzodiazepines, carbamazepine, topiramate and SSRIs appear to produce most of the currently recognized ocular problems. Psychiatrists, ophthalmologists and patients need to be aware of and prepared for any medication-induced adverse effect. Early prevention and intervention can avoid most of the serious and potentially irreversible ocular toxicities.

https://www.ncbi.nlm...les/PMC4723200/
Keep an eye on the SSRI: help avoid possible sight-threatening adverse events
Detailed discussion of various ocular side effects from SSRIs.
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Research Articles on ssris being Anxiogenic

anxiogenic - causing anxiety.

http://www.ncbi.nlm....pubmed/21397628
Research articles on ssri and causing anxiety

http://www.ncbi.nlm....pubmed/12527473
http://www.ncbi.nlm....pubmed/11485052
http://www.ncbi.nlm....pubmed/18454279
http://www.ncbi.nlm....pubmed/24155299
http://www.ncbi.nlm....pubmed/19440190
http://www.ncbi.nlm....pubmed/19840819
fluoxetine is acutely anxiogenic.
Many more articles are available on this ssri.

http://www.ncbi.nlm....pubmed/16971899
http://www.ncbi.nlm....pubmed/18830239
citalopram is anxiogenic.

http://www.ncbi.nlm....les/PMC2129095/
http://www.ncbi.nlm....pubmed/17524369
fluoxetine and citalopram is angiogenic in early stage of use.

http://www.ncbi.nlm....pubmed/22232580
http://www.ncbi.nlm....pubmed/10347793
http://www.ncbi.nlm....pubmed/21315769
Long term and short term anxiogenicity of fluoxetine

http://www.ncbi.nlm....pubmed/11271409
Paxil is anxiogenic.

http://www.ncbi.nlm....pubmed/11806866
http://www.ncbi.nlm....pubmed/11037770
sertraline and fluoxetine are angiogenic.

Drug data sheets on ssris.


citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital)
http://www.drugs.com...m-capsules.html
4% experience anxiety as a side effect.
http://www.ehealthme.../celexa/anxiety
8.6% report increased anxiety.

escitalopram (Lexapro, Cipralex, Seroplex, Esertia)
http://www.drugs.com...ph/lexapro.html
Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality
Side Effects - anxiety attacks
http://www.ehealthme...lexapro/anxiety
9.3% report anxiety as a side effect.


fluoxetine (Depex, Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (IND))
http://www.ehealthme...ess and anxiety
6.5% report anxiety as a side effect.
http://www.drugs.com...de-effects.html
Psychiatric side effects including hypomania, mania, transient psychosis, development of obsessive-compulsive symptoms, paranoid reaction, delusions, agitation, and a depersonalization syndrome have been reported.


fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox, Floxyfral)
http://www.ehealthme...maleate/anxiety
4.6% report it causes anxiety as a side effect.

http://www.rxlist.co...drug-center.htm
Call your doctor at once if you have any new or worsening symptoms such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), depressed, or have thoughts about suicide or hurting yourself.

http://www.drugs.com...de-effects.html
Psychiatric side effects including cases of hypomania and mania, apathy, indifference, disinhibition (without concurrent hypomania), hallucinations, paranoid, suicidal or antisocial ideation, abnormal thinking, and panic attacks have been reported.


paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc)
http://www.drugs.com...de-effects.html
Psychiatric side effects have frequently included anxiety (2% to 5%), agitation (2% to 5%),
http://www.ehealthme...s/paxil/anxiety
8.9% reported anxiety as a side effect.


sertraline (Zoloft, Lustral, Serlain, Asentra, Tresleen)
http://www.ehealthme...hloride/anxiety
6.6% report anxiety as a side effect.

http://www.drugs.com...de-effects.html
Psychiatric side effects including agitation and changes to hypomania have been observed infrequently. Although the drug has been reported to be an effective agent in the treatment of panic attacks, several cases of sertraline- induced panic attacks have been reported.
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Tachyphylaxis
Tachyphylaxis, also known as drug tolerance or"Prozac poop-out, is the condition where a patient becomes tolerant of a drug and its effectiveness declines.
https://www.ncbi.nlm...les/PMC4008298/
"...depressed patients with “true” antidepressant tachyphylaxis may be less responsive to new treatment interventions."

https://www.ncbi.nlm...pubmed/19571597
"The odds ratio indicates a 19.9% reduced likelihood of response with each prior antidepressant treatment" In otherwords for each antidepressant you have been on there is a 19.9% greater chance that the next AD will poop-out on you.

https://www.ncbi.nlm...pubmed/21851459
The cases of tolerance/tachyphylaxis were observed in 23% of patients and in 13 trials (22.4% of trials). All cases of tolerance occurred during monotherapy. No cases of tachyphylaxis were observed in the non-SSRI group (SNRI) while in the SSRI group, tolerance at some stage of the treatment was detected in 41.9%.

https://www.ncbi.nlm...pubmed/15960562
Rates of tachyphylaxis were significantly lower with the dual reuptake inhibitors venlafaxine and TCAs (3.7% of 82) compared to rates of tachyphylaxis with SSRIs (14.1% of 326).

https://www.ncbi.nlm...pubmed/18694599
The odds of responding to venlafaxine therapy decreased with an increasing number of prior antidepressant exposures.

Provided is a list of medications known to be subject to Poop-out.

SSRIs subject to tachyphylaxis

Citalopram hydrobromide (Celexa)
Escitalopram oxalate (Lexapro)
Fluvoxamine maleate (Luvox)
Paroxetine hydrochloride (Paxil)
Fluoxetine hydrochloride (Prozac)
Sertraline hydrochloride (Zoloft)
MAOIs subject to tachyphylaxis
・ Isocarboxazid (Marplan)
・ Phenelzine (Nardil)
・ Selegiline (Emsam)
・ Tranylcypromine (Parnate)
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Tardive Dyskinesia

Causes;
Tardive dyskinesia (TD) is an involuntary neurological movement disorder caused by the use of dopamine receptor blocking drugs that are prescribed to treat certain psychiatric or gastrointestinal conditions such as;
Chlorpromazine (Thorazine)
Fluphenazine (Prolixin)
Haloperidol (Haldol)
Thioridazine (Mellaril)
Trifluoperazine (Stelazine)
As well as;
Metoclopramide (Reglan)
Prochloroperazine (Compazine)
Benzhexol
Biperiden
Ethopropazine
Orphenadrine
Procyclidine
MAOIs: phenelzine
SSRIs: fluoxetine, sertraline
Trazodone
TCAs: amitriptyline, amitriptyline-perphenazine, amoxapine, doxepin, imipramine
Carbamazepine
Ethosuximide
Phenobarbital
Phenytoin
Various Antihistamines
Chloroquine
Bromocriptine
Carbidopa-levodopa
Levodopa
Alprazolam
Dopamine
Lithium
Estrogens
Amphetamine
Methylphenidate
Stimulants, have been associated with TD. Stimulants include caffeine, nicotine, guarana, ginseng, legal amphetamines, ephedrine, and illicit amphetamine and methamphetamine.

More likely to get it if you are;
Are a woman who has gone through menopause
Are over age 55
Abuse alcohol or drugs
Are African-American or Asian-American

Treatments
There are two FDA-approved medicines to treat tardive dyskinesia:
⦁ Valbenazine (Ingrezza)
⦁ Deutetrabenazine (Austedo)
Both of these medicines work in similar ways to regulate the amount of dopamine flow in brain areas that control certain kinds of movements. Both of these medicines can sometimes cause drowsiness.
Natural treatments
Ginko biloba
Melatonin
Vitamin B6 (Note - Vitamin B6 has a half life of 25 days and is easy to develop Vitamin B6 toxicity with supplements)
Vitamin E

Studies are ongoing to determine possible new drug therapies for the treatment of tardive dyskinesia. Choline, lithium, bromocriptine, baclofen, methyldopa, valproate, clonidine, propranolol, amantadine, clonazepam, and nifedipine have occasionally been helpful but in most cases do not improve dyskinesia. Tetrabenazine is often useful for symptomatic treatment of tardive dyskinesia and is currently available for use in the US. However, it carries the risk of causing or aggravating depression. Other experimental drugs are being tested to reduce or eliminate the symptoms of tardive dyskinesia.
Other therapeutic agents for which there is some anecdotal support include, levodopa (see carbidopa/levodopa), benzodiazepines, botulinium toxin, reserpine, tetrabenazine, and dopamine-depleting agents. Ondansetron, a selective 5-hydroxytryptamine-3 antagonist, has helped some individuals with TD. Discontinuance of anticholinergic therapy may relieve TD. A controversial strategy for treating TD is to continue or increase the dose of the dopamine antagonist.
https://www.ncbi.nlm...les/PMC5472076/
Medication-Induced Tardive Dyskinesia: A Review and Update (2017)
Treatments;
Medications and Supplements Used to Treat Tardive Dyskinesia
A number of medications and supplements have been identified that ameliorate TD symptoms.

Cholingergic Agents.
Cholinergic agents are used as muscle stimulants to diagnose myasthenia gravis and to treat glaucoma. These agents can also improve the Parkinsonian features of TD. Donepezil, a reversible acetylcholinesterase inhibitor, is currently the only cholinergic medication that has shown benefit against TD. Overall, however, cholinergic agents are not a widely accepted treatment for TD as sufficient evidence is lacking to suggest they are more helpful than other treatments.
Clozapine, Quetiapine, Olanzapine, and Apomorphine.
Clozapine, a serotonin and dopamine receptor antagonist, is an atypical APD used to treat schizophrenia. Clozapine is the best current medication recommended for patients who require antipsychotics and simultaneously have TD, as clozapine has been reported to reverse TD symptoms. Clozapine has been linked to TD; however, the incidence is much lower compared to other atypical APDs. Drugs with similar mechanisms of action such as quetiapine, a weak striatal dopamine antagonist, and olanzapine, a dopamine and serotonin receptor antagonist, have also been shown to be effective in ameliorating TD symptoms. Apomorphine, a dopamine receptor antagonist, can be given in conjunction with L-DOPA to decrease dyskinesias.

Tetrabenazine Analogs.
Tetrabenazine, a vesicular monoamine transporter inhibitor, decreases the severity of TD symptoms.However, tetrabenazine is rapidly metabolized and therefore needs to be administered frequently. Analogs of tetrabenazine such as valbenazine, a (+)-α-isomer of tetrabenazine, have been approved for clinical trials for the treatment of TD. In a phase IIb randomized, parallel, double-blind, placebo-controlled clinical trial of patients with moderate to severe TD, 67% of patients treated with valbenazine reported a “much improved” or “very much improved” Abnormal Involuntary Movement Scale score compared with 16% of patients taking placebo.
Clonazepam.
While certain benzodiazepines can cause TD, evidence suggests that some may be beneficial in treating TD. Sharma's proposed guidelines for treating TD include clonazepam and were successful in a patient who presented with TD symptoms after long-term treatment with trifluoperazine (a typical APD), citalopram, trihexyphenidyl, and propranolol. A case report published in 2001 related that 2 mg/day of clonazepam for 1 year successfully alleviated the TD symptoms of a 66-year-old female, and she did not develop tolerance during the 1-year period.
Propranolol.
Propranolol is a beta-adrenergic receptor antagonist used to treat high blood pressure, cardiac arrhythmias, and migraines. A retrospective study of 47 patients with TD that persisted for 17 months after discontinuation of APDs reported that low-dose propranolol appeared to be well tolerated in this patient population, and 64% of the patients saw an improvement in their TD symptoms.

Amantadine.
Amantadine is a noncompetitive glutamate receptor antagonist. It is postulated to work by increasing presynaptic release of dopamine and blocking presynaptic dopamine reuptake. Amantadine has been shown to be effective in treating L-DOPA–induced TD in patients with Parkinson disease.
Branched-Chain Amino Acids.
Some evidence suggests that an inability to clear ingested forms of the amino acid phenylalanine is associated with TD. Branched-chain amino acids (BCAAs) are reported to decrease TD symptoms because they decrease plasma phenylalanine by stimulating protein synthesis and insulin release. BCAAs also decrease the accumulation of tyrosine, another amino acid and an important precursor to dopamine, that reduces overall dopamine synthesis in the nervous system. Most important, BCAAs also seem to be effective at decreasing TD symptoms while an APD medication is still on board or the patient has a history of APD exposure. BCAAs are available over the counter in a flavored powder preparation to mix with water, so they may be a promising, practical, and inexpensive treatment for TD.

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Tardive Dyskinesia (Cont)

Ginkgo Biloba.
The American Academy of Neurology recommends clonazepam and ginkgo biloba, an extract of the ginkgo biloba tree leaf that is used as a dietary supplement, to enhance cognitive function to treat TD.
Antioxidant Medications and Supplements.
Because evidence suggests that oxidative stress may contribute to TD, several antioxidant medications and supplements are increasingly being used to treat TD: zonisamide, yi gan san (a Chinese herb), levetiracetam, melatonin, omega-3 fatty acids, piracetam, resveratrol, vitamin B6, and vitamin E. A comprehensive update on these medications is available in a 2015 review by Lerner et al.

Specific Medical research on alternate treatments
Melatonin
https://www.ncbi.nlm...pubmed/21950196
A randomized, double blind, placebo controlled design was used to determine the effectiveness of MEL (20 mg/day) during 12 weeks in 7 patients with TD. Six patients with TD were treated with placebo. In two patients treated with MEL a significant improvement (more than 60%) of the values of AIMS was detected. In the remainder five, as well as in the patients treated with placebo, no difference was observed during the 12 weeks.

https://www.ncbi.nlm...pubmed/10982197
Nineteen patients chronic DSM-IV schizophrenia of 31.3+/-7.0 years' duration, were randomly assigned in a double-blind, placebo-controlled, crossover trial to receive slow-release melatonin, 2 mg/day (low dosage), or placebo for 4 weeks. Supraphysiologic doses of melatonin do not positively affect tardive dyskinesia.

https://www.ncbi.nlm...pubmed/11695951
Using a double-blind, placebo-controlled, crossover study, we evaluated the efficacy of 10 mg/d of melatonin for 6 weeks in 22 patients with schizophrenia and TD. The decrease in AIMS score was 2.45 for the melatonin and 0.77 for the placebo treatment groups. This is the first clinical evidence for efficacy of melatonin in the treatment of TD.

Propranolol
https://www.ncbi.nlm...pubmed/27622970
Forty-seven patients were analyzed, mean age 63 years. Neuroleptics were discontinued in all patients and duration of TD at the time propranolol was initiated 17 months. Propranolol resulted in improvement in 64% and 77% of those had a moderate to complete or near-complete response. Mean daily dose was 69 mg and duration of therapy 14 months. Three patients stopped the propranolol due to adverse effects: hypotension (2), nightmares (1). Severity of TD and duration of propranolol therapy were associated with response.

https://www.ncbi.nlm.../pubmed/6124534
A double-blind, intensive case design was used to study the effect of propranolol on tardive dyskinesia. No short-term improvement was observed, but two of the four subjects responded to long-term propranolol use.

https://www.ncbi.nlm...01471-0028b.pdf
In October 1979 I thought itnmmight be worth trying propranolol to modify the annoying mouth movements. Initially, I prescribed 10 mg to be taken four times a day; I soon increased the dose to 40 mg to be taken twice a day. Over approximately 6 weeks the mouth movements decreased; propranolol was continued at 80 mg/d. I last saw the patient 1 week before the time of writing, when she stated that she had run out of the propranolol and had not bothered to renew the prescription. She found that the mouth movements returned quite rapidly; therefore, she immediately began taking propranolol again, 40 mg twice a day.

Branched-Chain Amino Acids
Definition - A branched-chain amino acid (BCAA) is an amino acid having aliphatic side-chains with a branch (a central carbon atom bound to three or more carbon atoms). Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine and valine.[1] Non-proteinogenic BCAAs include 2-aminoisobutyric acid.
https://www.ncbi.nlm...pubmed/12777270
Long-standing tardive dyskinesia were randomly assigned to receive branched-chain amino acids or placebo. Treatment frequency was three times a day, 7 days a week for 3 weeks. A robust and highly significant difference was observed between patients who received high-dose branched-chain amino acids (222 mg/kg of body weight t.i.d.) (N=18) and those who received placebo (N=18) in the percent change in tardive dyskinesia symptoms from baseline to the end of the 3-week trial. Significant and marked differences were seen between the two groups at the >/=30% and >/=60% levels of decrease in tardive dyskinesia symptoms.

https://www.ncbi.nlm...pubmed/10367552
A 2-week trial of a BCAA medical food administered three times a day was conducted in nine men with long neuroleptic treatment histories. Frequency counts of TD movements were collected by videotape throughout the trial and these tapes were analyzed in blind random sequence for both patient and time for TD symptom level changes subsequent to completion of the trial. A statistically significant decrease in the level of TD symptoms was observed for the sample. The symptom changes were also clinically significant in that six of the nine subjects had symptom decreases of at least 58%, with all subjects having a decrease of at least 38%.

https://www.ncbi.nlm...pubmed/14744176
TD evaluation at baseline and after 1 and 2 weeks of BCAA treatment given in the form of a drink administered 3 times daily. TD symptom decreases were substantial in 5 of the 6 participants, ranging from 40% to 65%. Two of the subjects received an additional course of treatment, and further reductions in TD symptoms over those seen in the 2-week trial were observed.

Omega-3 Fatty Acids
I found two reseqarch articles that both said there was no improvement in TD with the use of Omega 3 fatty acids.

Resveratrol
I found NO articles where resveratrol has been evaluated in the treatment of TD.

Calcium
https://www.ncbi.nlm.../pubmed/3227974
Serum calcium levels were measured in 25 chronically ill psychotic inpatients with involuntary movements, in comparison with 25 otherwise indistinguishable patients without such a syndrome. Those with involuntary movements were significantly more likely to have a serum calcium level below the normal range.

http://globalresearc...Article 019.pdf
Laboratory studies include....
B. Serum electrolytes- to omit abnormalities of sodium and calcium metabolism that may cause movement disorders.

https://pdfs.semanti...8f7d29d4683.pdf
The blood test showed a light hypermagnesaemia (2.5 mg/dL) not related to a large ingestion of magnesium nor with any symptom of renal failure and levels of calcium of 9.70 mg/dL, which are in the upper levels of normal concentration (normal values: 8.89 - 10.0).

The only treatment was removal of haloperidol treatment.

Forty-eight hours after hospital admission, the patient was discharged. At that time the levels of magnesium in blood were slightly reduced. The blood test was showing an haloperidol concentration of 0.4 μg/L, a maintained leucocytosis and anaemia. Calcium level was of 9 mg/dL, and blood magnesium levels were of 2.1 mg/dL, being both
value considered normal.

Our suggestion is to control the calcium and magnesium levels in
patients receiving a chronic haloperidol treatment to prevent these
crises.

http://europepmc.org...ct/med/18363098
There is involvement of calcium in triggering the oxidative damage and excitotoxicity, both of which play central role in haloperidol-induced orofacial dyskinesia and associated alterations.
Results of the present study indicate that haloperidol-induced calcium ion influx is involved in the pathogenesis of tardive dyskinesia

Magnesium
https://www.ncbi.nlm...pubmed/27816557
The co-administration of haloperidol and Mg supplementation prevented RS generation in cortex, striatum and SN, and PC levels in the SN.These outcomes indicate that Mg supplementation may be a useful alternative to prevent movement disturbances resulting of classic antipsychotic pharmacotherapy as haloperidol.
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Trazodone
https://www.ncbi.nlm...pubmed/25920951
Antidepressant-induced galactorrhea and increases in prolactin levels have rarely been reported. Trazodone can potentiate the serotonergic activity of citalopram. To our knowledge, no cases of galactorrhea associated with use of trazodone have been reported to date.

https://www.ncbi.nlm...les/PMC4418332/
These findings suggest that trazodone could be effective therapy for patients with OSA (obstructive sleep apnea) without worsening hypoxemia.

https://www.ncbi.nlm...pubmed/26017199
Trazodone and omeprazole interaction causing frequent second-degree Mobitz type 1 atrioventricular (AV) block (Wenckebach phenomenon) and syncope: a case report and literature review.
A 54-year-old man who was a former smoker, with dyslipidemia, coronary artery disease, and anxiety disorder developed lightheadedness and syncope the morning of admission. He was taking trazodone 50 mg daily, omeprazole 20 mg daily, and simvastatin 20 mg at bedtime. He doubled the dose of trazodone 50 mg on the night prior to presentation to calm his anxiety. An electrocardiogram revealed sinus rhythm at 60 beats per minute and second-degree Mobitz type 1 atrioventricular (AV) block with 5:4 AV conduction. Results of basic metabolic panel, thyroid-stimulating hormone, and chest radiograph were normal. A transthoracic echocardiogram revealed aortic valve sclerosis. We tested for Lyme disease given his history of hunting in the woods 8 months prior to presentation, but the titer was negative. Trazodone and omeprazole were discontinued. By the 3rd day of medication discontinuation, all symptoms had resolved and the frequency of second-degree AV Mobitz type 1 AV block had decreased to once per hour.

https://www.ncbi.nlm...pubmed/26088119
Although trazodone is approved and marketed in most countries worldwide for the sole treatment of Major Depressive Disorder, the use for this medication is very common for many other conditions, such as primary or secondary insomnia, Generalised Anxiety Disorder, Panic Disorder, Post-Traumatic Stress Disorder and Obsessive- Compulsive Disorder. Other, not officially approved, uses of trazodone include: the treatment of bulimia, benzodiazepine and/or alcohol dependence or abuse, fibromyalgia, degenerative diseases of the central nervous system such as dementia and other organic disorders, schizophrenia, chronic pain, and diabetic neuropathy. In addition, due to its 5HT2A receptor antagonistic action, trazodone may be used to prevent the occurrence of initial and long-term side effects of SSRI, such as anxiety, insomnia and sexual dysfunction.
https://www.ncbi.nlm...pubmed/26174731
It is very effective in the treatment of depression, in anxiety and insomnia. Its known side effects mainly occur with prolonged use of daily doses of 150-200 mg. The ability to enhance drowsiness may be associated with some risk in elderly patients. This clinical case illustrates an acute extrapyramidal event (movement disorders, like tardives) induced by a low dose of trazodone.

https://www.ncbi.nlm...pubmed/25376160
Prolonged-release trazodone was more effective than placebo in MDD and was well tolerated.

https://www.ncbi.nlm...pubmed/24023050
The bioactive intermediate metabolites of trazodone might cause hepatotoxicity (Liver toxicity).

https://www.ncbi.nlm...pubmed/27147406
Trazodone and milnacipran are the active antidepressant drugs that are being used in the treatment of psychiatric disorders. In this study, the in vitro genotoxic effects of trazodone and milnacipran have been determined in human peripheral blood lymphocytes by using chromosomal aberrations (CAs), sister chromatid exchanges (SCEs), micronuclei (MN), and comet assays. 3.13; 6.25; 12.50; 25.00; 50.00; and 75.00 μg/mL concentrations of trazodone and 2.50; 5.00; 10.00; 20.00; 30.00; and 40.00 μg/mL concentrations of milnacipran were used. Trazodone and milnacipran significantly increased the frequency of CAs and SCEs compared with the control. Both of the active ingredients raised the MN frequency in a dose-dependent manner. Mitotic index was significantly decreased, but replication and nuclear division indices were not affected at all treatments. Trazodone was statistically increased the mean comet tail intensity, tail length, and tail moment at three concentrations (6.25; 12.50; and 25.00 μg/mL) compared with control. Two highest concentrations (50 and 75 μg/mL) of trazodone were toxic in the comet assay. Milnacipran increased the comet tail intensity, tail length, and tail moment at all concentrations. It is concluded that trazodone and milnacipran have clastogenic, mutagenic, and cytotoxic effects on human lymphocytes in vitro.

https://www.ncbi.nlm...pubmed/26187900
The second-generation selective 5-HT2 receptor antagonists and reuptake inhibitors (SARIs) class antidepressants are known to have fewer cardiovascular side effects than the older ones. However, several case reports showed that trazodone, one of the second-generation SARIs, induces QT prolongation, cardiac arrhythmia, and ventricular tachycardia. Although these clinical cases suggested trazodone-induced cardiotoxicity, the toxicological actions of trazodone on cardiac action potentials (APs) beyond the human ether-a-go-go related gene (hERG) remain unclear. To elucidate the cellular mechanism for the adverse cardiac effects of trazodone, we investigated its effects on cardiac APs and ion channels using whole-cell patch clamp techniques in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and transiently transfected human embryonic kidney cells (HEK293) with cardiac ion channel complementary DNA. Trazodone dose-dependently decreased the maximum upstroke velocity (Vmax) and prolonged the AP duration, inducing early after depolarizations at 3 and 10 μM that triggered ventricular arrhythmias in hiPSC-CMs. Trazodone also inhibited all of the major ion channels (IKr, IKs, INa, and ICa), with an especially high inhibitory potency on hERG. These data indicate that the prolonged AP duration and decreased Vmax due to trazodone are mainly the result of hERG and sodium ion inhibition, and its inhibitory effects on cardiac ion channels can be exhibited in hiPSC-CMs.

https://www.ncbi.nlm...les/PMC3987616/
A 26-year-old female outpatient presenting with a depressive state suffered from auditory hallucinations at night. Her auditory hallucinations did not respond to blonanserin or paliperidone, but partially responded to risperidone. In view of the possibility that her auditory hallucinations began after starting trazodone, trazodone was discontinued, leading to a complete resolution of her auditory hallucinations.

https://www.ncbi.nlm...pubmed/23661283
Acute treatment of mirtazapine impaired road-tracking performance and increased sleepiness, but sedative effects disappeared under repeated administrations. Trazodone did not affect driving performance or cognitive function under acute or repeated administrations.

https://www.ncbi.nlm...pubmed/23450804
The number of individual impairment clues detected is increased with trazodone. Trazodone 100 mg may cause cognitive driving impairment.

https://www.ncbi.nlm...les/PMC3693429/
Trazodone is effective in controlling a wide range of symptoms of depression, while avoiding the negative effects on sleep seen with SSRI antidepressants. The recently approved prolonged-release formulation should provide further optimization of this antidepressant and may be useful for enabling an appropriate therapeutic dose to be administered with improved patient compliance.

https://www.ncbi.nlm...les/PMC3165092/
Trazodone produced small but significant impairments of short-term memory, verbal learning, equilibrium, and arm muscle endurance across time points. Relative to placebo across test days, trazodone was associated with fewer nighttime awakenings, minutes of Stage 1 sleep, and self-reports of difficulty sleeping. On Day 7 only, slow wave sleep was greater and objective measures of daytime sleepiness lower with trazodone than with placebo. Although trazodone is efficacious for sleep maintenance difficulties, its associated cognitive and motor impairments may provide a modest caveat to healthcare providers.

https://www.ncbi.nlm...pubmed/22239013
Its performance was analyzed in individuals dependent on alcohol, benzodiazepines and opiates, as well as mixed addictions. Also raised the problem of influence of trazodone on the experience of pain, which maybe helpful in relieving withdrawal symptoms. The data show a positive effect of trazodone in individuals addicted to the SPA, although the mechanism by which trazodone works in the body is very complex and not yet fully understood. Its advantage is the relatively small panel of side effects. Although many of the analyzed studies were not placebo-controlled, the results are so promising that you can recommend on the basis of trazodone therapy in individuals addicted to the SPA.

https://www.ncbi.nlm...pubmed/22574377
Yimusake combined with trazodone hydrochloride is highly efficacious for primary PE (premature ejaculation).

https://www.ncbi.nlm...pubmed/21740694
We found that patients taking trazodone can produce urine with sufficient m-CPP to result in false-positive Amphetamines II results.

https://www.ncbi.nlm...pubmed/22732813
The purpose of the study was to highlight the cytoarchitectural changes in the frontal cortex and hippocampus by comparing two antidepressant substances: amitriptyline with a strong anticholinergic effect and trazodone, without anticholinergic effect. The superior neuroprotective qualities of trazodone for the frontal cortex, hippocampus and dentate gyrus are revealed. The particular neurobiological vulnerability of depression in women requires a differentiated therapeutic approach, avoiding the use of antidepressants with anticholinergic action.

https://www.ncbi.nlm...pubmed/21575194
Trazodone significantly improved fibromyalgia severity and associated symptomatology. Its combination with pregabalin potentiated this improvement and the tolerability of the drugs in association was good.

https://www.ncbi.nlm...pubmed/22115401
Various other attributes of trazodone, including interaction with adrenergic receptors, formation of an active metabolite with potent serotonergic activity, low abuse potential and putative utility in various disorders, warrant further exploration. The adverse effects of trazodone generally mirror its serotonergic activity and include sedation, headache, sweating, weight changes and gastrointestinal effects such as nausea and vomiting. Clinicians and patients should be cognizant of the risk for potential, but rare, cardiovascular adverse effects of trazodone.

https://www.ncbi.nlm...pubmed/21220793
It is generally approved for the treatment of major depression, its efficacy is well-documented in elderly patients, and it has been widely used for replacement of benzodiazepines or benzodiazepine-type sleeping drugs due to its anxiolytic efficacy and sleep normalizing effect in depression. Trazodone was further found to be clinically useful in generalized anxiety disorder, agitation of patients with dementia and organic disorders, chronic pain disorders, alcohol and benzodiazepine dependence. Tolerability of trazodone is comparable to the novel antidepressants. It is weight neutral and does not decrease sexual function

https://www.ncbi.nlm...les/PMC2945951/
Trazodone markedly improved sleep quality, with large effect sizes in total PSQI score as well on sleep quality, sleep duration and sleep efficiency. Significant improvement, although with moderate effect sizes, were also observed in total FIQ scores, anxiety and depression scores (both HADS and BDI), and pain interference with daily activities. Unexpectedly, the most frequent and severe side effect associated with trazodone in our sample was tachycardia, which was reported by 14 (21.2%) patients

https://www.ncbi.nlm...pubmed/20712254
Sexual dysfunctions may be main cause of social disability. The knowledge of the rates of occurrence of sexual dysfunctions in the general population and the primary risk factors for these conditions is very important to assist in assessing the risk and planning treatment. Sexual dysfunctions are highly prevalent in our society worldwide, and that the occurrence of sexual dysfunctions increases directly with age for both men and women. Specific medical conditions and health behaviors represent major risk factors for sexual disorders. Trazodone is sedative antidepressant drug, which is effective, safe, fast acting, with a few side effects, with proved efficiency in the treatment of sexual dysfunction.

https://www.ncbi.nlm...pubmed/15816789
Evidence for the efficacy of trazodone in treating insomnia is very limited; most studies are small, conducted in populations of depressed patients, raise issues of design, and often lack objective efficacy measures. Side effects associated with trazodone are not inconsequential, with a high incidence of discontinuation due to side effects, such as sedation, dizziness, and psychomotor impairment, which raise particular concern regarding its use in the elderly. There is also some evidence of tolerance related to use of trazodone.

https://www.ncbi.nlm...pubmed/15291651
It is concluded that there are very few data to suggest that trazodone improves sleep in patients without mood disorder, though it does increase total sleep in patients with major depressive disorder. There are virtually no dose-response data for trazodone vis-à-vis sleep and, similarly, no available data on tolerance to its possible hypnotic effects. Areas of concern with its use include reports of significant dropout rates and induction of arrhythmias, primarily in patients with histories of cardiac disease, as well as the development of priapism (a potentially painful medical condition in which the erect penis does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours).
.
https://www.ncbi.nlm...pubmed/11518472
Trazodone appears effective for the treatment of insomnia and nightmares associated with chronic PTSD. However, controlled trials are needed before any definite conclusions can be drawn. The higher than expected occurrence of priapism warrants clinicians asking directly about this side effect.

https://www.ncbi.nlm.../pubmed/9315494
In a group of patients, that was not selected on the basis of the etiology of the erectile dysfunction, nor selected on the duration of the complaint, the efficacy of trazodone 150 mg/d, could not be shown.

https://www.ncbi.nlm.../pubmed/8057411
The effects of trazodone on penile erection may be due to a peripheral alpha adrenoceptor antagonism and central unknown mechanism. We conclude that trazodone may prove an effective treatment for impotent patients.

https://www.ncbi.nlm.../pubmed/3284752
Although unwanted effects were generally mild, the incidence of dizziness was greater in those patients receiving trazodone. Caution is advised, however, when prescribing either drug to patients with transient cerebral ischaemic attacks or those with coronary artery disease receiving medication.

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Trazodone (Cont.)

http://www.lb7.uscou...IED/10-1191.pdf
Trazodone may cause side effects. Tell your doctor if any of these symptoms are severe or
do not go away:
headache or heaviness in head
nausea
vomiting
bad taste in mouth
stomach pain
diarrhea
constipation
changes in appetite or weight
weakness or tiredness
nervousness
decreased ability to concentrate or remember things
confusion
nightmares
muscle pain
dry mouth
sweating
blurred vision
tired, red, or itchy
Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately:
chest pain
fast, pounding, or irregular heartbeat
shortness of breath
fever, sore throat, chills, or other signs of infection
hives
skin rash
itching
difficulty breathing or swallowing
swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
hoarseness
decreased coordination
uncontrollable shaking of a part of the body
numbness, burning, or tingling in the arms, legs, hands, or feet
dizziness or lightheadedness
fainting
painful erection that lasts longer than normal
Trazodone may cause painful, long lasting erections in males. In some cases emergency
and/or surgical treatment has been required and, in some of these cases, permanent damage can occur.

https://www.drugs.co...de-effects.html
In Summary
Commonly reported side effects of trazodone include: blurred vision, dizziness, drowsiness, nausea, vomiting, headache, and xerostomia. Other side effects include: syncope, edema, diarrhea, ataxia, insomnia, sedation, confusion, tachycardia, and hypotension.
More common:
⦁ Blurred vision
⦁ confusion
⦁ dizziness
⦁ dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
⦁ lightheadedness
⦁ sweating
⦁ unusual tiredness or weakness
Less common:
⦁ Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
⦁ confusion about identity, place, and time
⦁ decreased concentration
⦁ fainting
⦁ general feeling of discomfort or illness
⦁ headache
⦁ lack of coordination
⦁ muscle tremors
⦁ nervousness
⦁ pounding in the ears
⦁ shortness of breath
⦁ slow or fast heartbeat
⦁ swelling
Rare:
⦁ Skin rash
⦁ unusual excitement
Severity: Minor
Some trazodone side effects may not need any medical attention. As your body gets used to the medicine these side effects may disappear. Your health care professional may be able to help you prevent or reduce these side effects, but do check with them if any of the following side effects continue, or if you are concerned about them:
More common:
⦁ Dry mouth (usually mild)
⦁ muscle or bone pain
⦁ trouble sleeping
⦁ trouble with remembering
⦁ unpleasant taste
Less common:
⦁ Constipation
⦁ continuing ringing or buzzing or other unexplained noise in the ears
⦁ diarrhea
⦁ hearing loss
⦁ muscle aches or pains
⦁ weight loss
For Healthcare Professionals
Applies to trazodone: compounding powder, oral tablet, oral tablet extended release
General
The most commonly reported side effects were dry mouth, nausea, vomiting, drowsiness, dizziness/light-headedness, headache, and nervousness.
Cardiovascular
Common (1% to 10%): Hypertension, hypotension, syncope, tachycardia, palpitations
Frequency not reported: Sinus bradycardia, chest pain, ventricular couplets
Postmarketing reports: Cardiospasm, cerebrovascular accident, congestive heart failure, vasodilation, conduction block, orthostatic hypotension, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, ventricular ectopic activity, prolonged QT interval, torsade de pointes, ventricular tachycardia.
Psychiatric
Common (1% to 10%): Anger/hostility, excitement, insomnia, nightmares/vivid dreams
Frequency not reported: Hallucinations/delusions, mania/hypomania, impaired speech, suicidal ideation, disorientation, aggressive reaction, withdrawal syndrome
Postmarketing reports: Abnormal dreams, agitation, anxiety, paranoid reaction, psychosis.
Nervous system
Very common (10% or more): Drowsiness (up to 40.8%), dizziness/light-headedness (up to 28%), headache (up to 19.8%), nervousness (up to 14.8%)
Common (1% to 10%): Confusion, decreased concentration, disorientation, impaired memory, incoordination, paresthesia, tremors
Frequency not reported: Akathisia, muscle twitches, numbness, serotonin syndrome, convulsion, neuroleptic malignant syndrome, vertigo, restlessness, decreased alertness, cognitive/motor impairment
Postmarketing reports: Aphasia, ataxia, extrapyramidal symptoms, grand mal seizures, stupor, tardive dyskinesia, myoclonus,
Genitourinary
Common (1% to 10%): Decreased libido, delayed urine flow, early menses
Frequency not reported: Hematuria, impotence, increased libido, increased urinary frequency, missed periods, retrograde ejaculation
Postmarketing reports: Breast enlargement or engorgement, clitorism, lactation, priapism, urinary incontinence, urinary retention
Hematologic
Frequency not reported: Anemia, hemolytic anemia, granulocytosis, thrombocytopenia, eosinophilia, leucopenia
Postmarketing reports: Leukocytosis, methemoglobinemia
Metabolic
Common (1% to 10%): Decreased appetite, weigh gain/loss
Frequency not reported: Increased appetite, anorexia, hyponatremia
Ocular
Very common (10% or more): Blurred vision (up to 14.7%)
Common (1% to 10%): Red/tired/itching eyes
Frequency not reported: Angle-closure glaucoma
Postmarketing reports: Diplopia
Dermatologic
Common (1% to 10%): Sweating/clamminess
Frequency not reported: Hyperhidrosis
Postmarketing reports: Alopecia, leuconychia, pruritus, psoriasis, rash, urticaria
Endocrine
Postmarketing reports: Hirsutism, inappropriate ADH syndrome
Gastrointestinal
Very common (10% or more): Dry mouth (up to 33.8%), nausea/vomiting (up to 12.7%)
Common (1% to 10%): Constipation, abdominal/gastric disorder, bad taste, diarrhea
Frequency not reported: Flatulence, increased salivation, dyspepsia, stomach pain, gastroenteritis, paralytic ileus
Postmarketing reports: Increased amylase
Hepatic
Postmarketing reports: Cholestasis, hyperbilirubinemia, jaundice, liver enzyme alterations
Hypersensitivity
Frequency not reported: Allergic reactions[
Musculoskeletal
Common (1% to 10%): Musculoskeletal aches/pains
Frequency not reported: Limb pain, back pain, myalgia, arthralgia
Other
Very common (10% or more): Fatigue (up to 11.3%)
Common (1% to 10%): Edema, malaise, tinnitus
Frequency not reported: Chills, fever
Postmarketing reports: Unexplained death, weakness
Respiratory
Common (1% to 10%): Shortness of breath, nasal/sinus congestion
Frequency not reported: Dyspnea
Postmarketing reports: Apnea
References
1. "Product Information. Desyrel (trazodone)." Bristol-Myers Squibb, Princeton, NJ.
2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
It is possible that some side effects of trazodone may not have been reported. These can be reported to the FDA. Always consult a healthcare professional for medical advice.

http://link.springer...45?view=classic
http://www.ncbi.nlm..../pubmed/3624211
http://www.ncbi.nlm..../pubmed/8056996
Three cases developed withdrawal symptoms of trazodone despite gradual discontinuation of therapeutic doses of the drug. This report suggests that effects of trazodone and its metabolite m-chlorophenylpiperazine on the serotonergic system, which may result in noradrenergic rebound after discontinuation, and short half-lives of these compounds are involved in the development of these symptoms. From a clinical point of view, we suggest that trazodone should be tapered off at a very slow rate.
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Trintellix
Trintellix Withdrawal (Trintellix was previously known as Brintellix.)
http://mentalhealthd...long-they-last/
Trintellix Withdrawal Symptoms List
Below is a list of withdrawal symptoms that you may experience upon discontinuation of Brintellix. Understand that not everyone will experience every symptom listed below. The number of symptoms experienced as well as the severity is highly subject to individual variation.
⦁ Anger: When quitting any antidepressant, it is common to experience anger. The drug has likely altered your neurotransmission, making it difficult to produce adequate levels of serotonin. Outbursts of anger were reported as a “common” discontinuation symptom in clinical trials. Fortunately, you will likely notice your anger subsiding as you plod through withdrawal.
⦁ Anxiety: Upon discontinuation of any drug that has influenced serotonergic functions within the brain, you may feel anxiety. The anxiety may be mild or more extreme during the early stages of withdrawal. If you feel more anxious than usual, and have recently stopped this drug, it is likely due to the fact that your neurochemistry needs to readjust, specifically that which involves serotonin.
⦁ Brain zaps: Many people experience electrical shock sensations called “brain zaps” when they quit taking an antidepressant or skip a dose. In most cases, these can be lessened by conducting a gradual taper off of Brintellix. Despite the fact that these are highly uncomfortable sensations, they will eventually pass.
⦁ Concentration problems: Some individuals may notice a slight degree of cognitive enhancement from this medication. Upon discontinuation, not only will the enhancement disappear, but you may actually notice significant concentration problems. This is mostly a result of your brain trying to function without the drug. In the meantime, you’ll likely experience “brain fog.”
⦁ Depression: Taking an antidepressant may help depression, but when you quit, not only can you expect your original depression to return, you may actually experience a more severe version. Pre-drug depression and discontinuation depression are typically two different experiences. When you discontinue Brintellix, your brain will be chemically imbalanced as a result of the drug – thus leading to a different, potentially more severe depression.
⦁ Depersonalization: Do you now feel like you are “not yourself?” If you feel depersonalized, it is likely due to your brain attempting to sort out the chemical changes that were created by the drug. If you are highly stressed, this may further enhance the feelings of depersonalization. Just know that you will eventually feel like yourself again; it may take some time.
⦁ Dizziness: A very common withdrawal symptom associated with every antidepressant is that of dizziness. Your brain had become accustomed to receiving the drug for its functioning, and when you discontinue, certain neurological functions become altered – leading to dizziness.
⦁ Fatigue: Regardless of whether this drug had a pro-energy effect or made you tired, fatigue often ensues upon discontinuation. This is a medication that affected both serotonin and norepinephrine. Your nervous system had relied on the drug to provide it with some sort of energy, and when you quit taking it, your nervous system was still expecting it – thus leaving you tired.
⦁ Flu-like symptoms: Some individuals may feel achy, have a headache, feel nauseous, and may vomit upon discontinuation. The combination of all withdrawal symptoms may feel somewhat similar to the flu. Although it’s likely not nearly as severe as the flu, it certainly can make you feel sick.
⦁ Headaches: Most people experience some sort of headache when they quit this medication. The headache may be difficult to deal with, but is something that most people have to put up with. If it becomes unbearable, make sure you are drinking enough water, getting plenty of sleep, and eating right. Consider some over-the-counter headache relief if the headache is intense.
⦁ Insomnia: Many individuals find that when they quit this drug, they are unable to sleep at night. In some cases the insomnia can be mitigated with natural supplements like melatonin and/or simply engaging in relaxation prior to bed. Over time, your sleep cycle and circadian rhythm will reset itself.
⦁ Irritability: It is common to feel irritable when you discontinue this antidepressant. Every little “thing” may trigger anger or an irritable reaction, especially during the early stages of withdrawal. Do your best to realize that your feelings of anger and heightened stress will eventually subside. Although you may not be able to control the feeling of irritability, you can control how you express it.
⦁ Mood swings: Another reportedly common symptom of withdrawal is that of mood swings. Certain days you may feel alright, and others you may feel like total crap. One minute you’re angry, the next you are agitated and depressed. Understand that mood swings will continue to occur until your neurochemistry recalibrates itself.
⦁ Muscle tension: Another extremely common symptom to experience during withdrawal is muscle tension. Additionally, your muscles may also feel sore, achy, and weak. The tension may make it difficult to relax or stay calm. Engaging in relaxation exercises and/or practicing progressive muscular relaxation can be helpful.
⦁ Nausea: You may feel more nauseous than usual after you’ve quit Brintellix. In most cases, the nausea doesn’t last more than a couple weeks. Most people that experience nausea notice that it substantially decreases by the second or third week of their withdrawal.
⦁ Runny nose: Most antidepressants do not result in a “runny nose” upon discontinuation, but this one does. You may need to stock up on some tissue if this is a problem and over time, it will subside. This is a relatively odd withdrawal symptom, but apparently one of the more common ones associated with Brintellix discontinuation.
⦁ Suicidal thoughts: It is common to experience an increase in suicidal thoughts during withdrawal from Brintellix. It should be stated that you should seek immediate medical attention if you are unable to cope with these thoughts. If you had these thoughts prior to taking this drug, you likely won’t be able to distinguish between those resulting from withdrawal and those resulting from your original depression. However those that hadn’t experienced these thoughts pre-drug and now do after quitting will understand.
⦁ Sweating: If you sweat profusely during withdrawal, realize that this is your body’s way of detoxifying itself. Your nervous system may be slightly shocked now that it is attempting to function without the Brintellix. Concurrently your hormone levels may be altered as well (e.g. cortisol) which may contribute to the sweating.
⦁ Vomiting: In some cases, people can actually feel so nauseous that they vomit upon discontinuation. The vomiting doesn’t generally continue for more than a few days. This is a very uncomfortable symptom that is fortunately less common than others.
Note: It is known that Trintellix stays in your system for between 13 and 16 days after you’ve discontinued.  For this reason, many people notice that discontinuation symptoms often become more severe during the second or third week of withdrawal.
Withdrawal lasts 3 to 9 months.

Trintellix Information
Wiki - Vortioxetine hydrobromide (trade name Trintellix) is an atypical antidepressant known as serotonin modulators and stimulators.
Side effects - The most common side effects reported with vortioxetine are nausea, diarrhea, dry mouth, constipation, vomiting, flatulence, dizziness, and sexual dysfunction.
Incidence of sexual dysfunction is higher in patients taking vortioxetine than in people taking placebos but appears to be lower than in people taking most other antidepressants
Half-life 66 hours.
Vortioxetine was previously trademarked as Brintellix in the United States, but on May 2, 2016, the US FDA approved a name change to Trintellix in order to avoid confusion with the blood-thinning medication Brilinta (ticagrelor).
IMPORTANT - Vortioxetine has been studied in several clinical trials as a potential treatment for general anxiety disorder; it is not effective.

https://www.ncbi.nlm...pubmed/27807822
Across three large, placebo-controlled studies in adults with recurrent MDD (Major Depressive Disorder), short-term treatment with vortioxetine almost always resulted in statistically significant and clinically meaningful improvements in performance on two objective measures that together cover a broad range of cognitive domains, including executive function, attention, processing speed, learning and memory.
In general, the beneficial effects of vortioxetine on these measures were largely independent of its effect on improving depressive symptoms. Based on the available data, therefore, vortioxetine is a useful treatment option in patients with MDD where impaired cognitive function is apparent.

https://www.ncbi.nlm...pubmed/25145538
It is associated with improved cognitive function in patients with MDD; this does not occur solely via improvement in depressive symptom severity. It is well tolerated, but is associated with significantly increased sexual dysfunction at the highest dosage; however, vortioxetine was shown to improve previous-treatment-emergent sexual dysfunction in patients with well-treated MDD to a greater degree than escitalopram.

https://www.ncbi.nlm...pubmed/24676550
Vortioxetine is an effective agent for the treatment of MDD, but it does not have any clear advantages over other available treatment options.

https://www.ncbi.nlm...pubmed/26035186
Of the 1,111 subjects screened, 469 subjects were randomized: 160 to placebo, 157 to vortioxetine 10 mg, and 152 to vortioxetine 15 mg. Differences from placebo in the primary efficacy end point were not statistically significant for vortioxetine 10 mg or vortioxetine 15 mg. (Note - no significant improvement over placebo) Nausea, headache, dry mouth, constipation, diarrhea, vomiting, dizziness, and flatulence were reported in ≥ 5% of subjects receiving vortioxetine. Discontinuation due to adverse events (side effects) occurred in 7 subjects (4.4%) in the placebo group, 8 (5.2%) in the vortioxetine 10 mg group, and 12 (7.9%) in the vortioxetine 15 mg group. ASEX total scores were similar across groups. There were no clinically significant trends within or between treatment groups on the laboratory values, electrocardiogram, or vital sign parameters.
CONCLUSIONS:
In this study, vortioxetine did not differ significantly from placebo on MADRS total score after 8 weeks of treatment in MDD subjects.

https://www.ncbi.nlm...pubmed/25874839
Vortioxetine was significantly more effective than placebo for acute treatment of major depressive disorder (MDD). Although treatment effect estimates varied substantially between studies, a dose effect was not observed. Vortioxetine does not appear to be more effective, and is potentially less effective, than an SNRI.
The most common adverse events were nausea and vomiting which increased in frequency with higher doses.

https://www.ncbi.nlm...pubmed/25350320
We included 7 published and 5 unpublished short-term (6-12 wk) RCTs in our meta-analysis. Vortioxetine was significantly more effective than placebo. Those treated with vortioxetine did not differ significantly from those treated with selective norepinephrine reuptake inhibitors (SNRI). Discontinuation owing to lack of efficacy was significantly less common among those treated with vortioxetine than among those who received placebo, whereas discontinuation owing to adverse events was significantly more common among those treated with vortioxetine than among those receiving placebo. There was no significant difference in discontinuation rates between vortioxetine and comparators (other antidepressants) owing to inefficacy whereas discontinuation owing to AEs was significantly less common in the vortioxetine than in the comparator group .


https://www.ncbi.nlm...pubmed/26020712
Of the 1075 patients enrolled, 1073 received at least one dose of vortioxetine and 538 (50.0%) completed the study. A total of 537 patients withdrew early, with 115 (10.7% of the original study population) withdrawing because of TEAEs (side effects). Long-term treatment with vortioxetine was well tolerated; the most common TEAEs (≥10%) were nausea and headache. Laboratory values, vital signs, and physical examinations revealed no trends of clinical concern. The mean Montgomery-Åsberg Depression Rating Scale total score was 19.9 at the start of the extension study and 9.0 after 52 weeks of treatment (observed cases). Similar improvements were observed with the Hamilton Anxiety Scale (Δ-4.2), the Clinical Global Impression Scale-Severity of Illness (Δ-1.2), and the Sheehan Disability Scale (Δ-4.7) total scores after 52 weeks of treatment (observed case). In this 52-week, flexible-dose OLE study, 15 and 20 mg vortioxetine were safe and well tolerated. After entry into this study, patients continued to show improvement in depression and anxiety symptoms, as well as overall functioning, throughout the treatment period.

https://www.ncbi.nlm...les/PMC3979887/
Includes a comparison to Cymbalta.
Overall, abrupt discontinuation of vortioxetine was well tolerated and the low DESS total score and the nature of the discontinuation symptoms suggest that down-tapering of vortioxetine is not needed. This might be because of its relatively long apparent half-life of 66 h.
The withdrawal rate due to all reasons during the entire study was 16.6% [15.8% (placebo), 22.5% (vortioxetine 15 mg), 17.2% (vortioxetine 20 mg) and 10.9% (duloxetine)]

Contains a table of all reported adverse events.
The most common AEs reported by at least 5% of patients in either of the vortioxetine groups and for which the incidence was numerically higher than that in the placebo group were nausea, headache, diarrhea (20 mg) and dry mouth (20 mg). In the duloxetine group, AEs with an incidence of greater than 5% and higher in the placebo group were nausea, headache, dizziness, dry mouth, hyperhidrosis, diarrhea and fatigue.
The incidence of AEs related to sexual dysfunction (orgasm abnormal, anorgasmia, ejaculation delayed, ejaculation disorder, libido decreased, erectile dysfunction, orgasmic sensation decreased, sexual dysfunction) was 2.5% (placebo), 2.0% (vortioxetine 15 mg), 4.0% (vortioxetine 20 mg) and 3.5% (duloxetine) of patients.
Suicidal ideation was reported by 11.4% (placebo), 9.9% (vortioxetine 15 mg), 9.3% (vortioxetine 20 mg) and 6.1% (duloxetine) of patients.
Two patients took an intentional overdose of zolpidem (vortioxetine group) or zolpidem and lormetazepam (duloxetine group).
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[fishinghat]

Valsartan
http://www.druginfor...l symptoms.html
45 Reports to FDA on withdrawal symptoms. Please note the 6.7% death rate.

https://www.ehealthm...rawal-syndrome/
20,086 people reported to have side effects when taking Valsartan.
Among them, 36 people (0.18%) have Withdrawal syndrome
http://www.medicatio...ovan-withdrawal
Abrupt Diovan Withdrawal
4 comments
Dman11111 - what did you end up doing with the diovan \ive been taping off and the feeling is wonderful yes my bp is high again but im going to try alternative nature stuff the side effects were almost killing me now everything is reversing unfornatly the bp is higher again
Garrettgla - i cannot tell you how dizzy i was on the diovan. i asked the dr. she said taper off over 2 days and immediately go back on the atenolol 25mg. older medication. i did and i gotta tell u i feel so much better. it's cheap too. its keeping my blood pressure low too. so im happy. sorry i waited so long to go off the diovan.
Debgibsonmt - After a year and ahalf of taking diovan trying to get off is a nightmare. Blood pressure totally erratic even though all blood test show extremely low cholesteral and a CRP of less than 1. So, diovan is extremely addictive and the body seems to loose it's ability to regulate it's own blood pressure. Which, I'm sure, is what the drug company's want.
Dman11111 - Yes i agree. I am now on the generic of diovan. Because the drug comanies are trying to save money. It is painfully impossible to try and quit diovan. Im sooo glad someone actually agreed with me that it is highly addictive. It would take months for the body to go back to its own regualtion....let me know if you successfully quit ....i found the withdrawl to hard to take. At least right now. Maybee with time i can figure out an alternative. Once again. Highly addictive .......and they will tell you its not! We are living it!!!

https://www.peoplesp...-a-new-scandal/
Report on the falsifying of data on Valsartan in order to get FDA approval. Five life threatening side effects were hidden.

https://www.accessda...1283s018lbl.pdf
Abrupt withdrawal of valsartan has not been associated
with a rapid increase in blood pressure.

I found NO scientific articles dealing with the subject.
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