Effexor Venlafaxine Withdrawal Breakthrough.

If you wish to remain on Effexor but eliminate current Effexor withdrawal side effects, click here.

If you want to taper off the Effexor and you are not sure where to start, you can click here and read the bestselling book, How to Get Off Psychoactive Drugs Safely or send Jim Harper an email at [email protected] and he will guide you through the process of Effexor withdrawal.

If you are experiencing brain zaps, electrical jolts in the head, click here

Effexor Withdrawal Symptoms

If you are experiencing brain zaps (electrical jolt in the head) click here for the solution. The Omega 3 Supreme is the only answer. Take 2 softgels in the morning and 2 more at noon and the brain zaps should stop within 3 days. Most likely in hours. Click here for Omega 3 Supreme.

1: Introduction to Effexor Withdrawal.

Effexor, also known as Venlafaxine, is a medication used to treat depression and anxiety disorders. While it can be effective in managing symptoms, many individuals who take Effexor find that they become dependent on the medication. This dependence can lead to withdrawal symptoms when they try to stop taking the medication. Withdrawal from Effexor can be a challenging experience, and it’s important to understand the process in order to manage symptoms effectively.

Part 2: Common Effexor Withdrawal Symptoms.

Withdrawal from Effexor can cause a range of physical and emotional symptoms. Some of the most common physical symptoms include headaches, dizziness, nausea, and fatigue. Individuals may also experience flu-like symptoms, such as muscle aches and chills. Emotional symptoms can include irritability, anxiety, and depression. In some cases, individuals may experience suicidal thoughts or behaviors.

Part 3: Timeline of Effexor Withdrawal.

The timeline of Effexor withdrawal can vary from person to person, depending on factors such as the dose and duration of medication use. Generally, withdrawal symptoms can begin within a few hours of the last dose and can last for several weeks or even months. The first few days of withdrawal are typically the most intense, with symptoms peaking around day three or four. Symptoms may gradually improve after the first week or two, but some individuals may experience protracted withdrawal, in which symptoms persist for several months or longer.

Part 4: Managing Effexor Withdrawal Symptoms.

There are several strategies that can help individuals manage withdrawal symptoms from Effexor. One of the most effective is to taper off the medication slowly, under the guidance of a healthcare provider. This allows the body to adjust gradually to lower doses of the medication, minimizing the severity of withdrawal symptoms. Other strategies that can help manage symptoms include getting regular exercise, practicing relaxation techniques, and getting support from friends and family. In 1999, The Road Back found; 50% of the people trying to withdrawal off an antidepressant could make it through withdrawal but they still suffered withdrawal side effects. This withdrawal was accomplished by only using a 10% reduction of the medication every 2 weeks. Of the 50% that could make it off the antidepressant, 40% went back on the antidepressant because the withdrawal symptoms were too severe, and they saw no hope in ever living a normal life again.

The Road Back began investigating other options than a slow and gradual withdrawal. In 2000, The Road Back began a trial using a whey protein shown to increase the glutathione in the body. The success was immediate. We found; 90% of those that went back on their antidepressant could now go off their antidepressant, do very well with the taper and remain off the antidepressant.

During the next 10 years, The Road Back continued testing other nutritional supplements to improve the program and during the decade several changes were made to the supplements recommended.

In 2010, a major breakthrough was accomplished. In 2010, our founder Jim Harper, discovered a gene that becomes altered with the use of every psychotropic medication. This gene, the JNK gene, was virtually responsible for most every psychotropic medication withdrawal side effect. Not only during withdrawal but also when a person is taking the full dosage of the medication as prescribed.

Part 5: Effexor Withdrawal, where we are in 2023, and The Road Back Program?

The Road Back Program uses formulated nutritional supplements to address; the JNK gene, glutathione as well as aquaporins to help eliminate Effexor withdrawal. Over 19 million people throughout the world have now used The Road Back Program to get their life back.

Part 6: Risks of Effexor Withdrawal.

While most individuals who withdraw from Effexor will experience only mild to moderate symptoms, there are some risks associated with the process. In some cases, withdrawal can lead to severe or even life-threatening symptoms, such as seizures or suicidal thoughts. It’s important to work closely with a healthcare provider to manage withdrawal safely and effectively.

Part 7: Conclusion.

Effexor withdrawal can be a challenging experience, but it’s important to remember that symptoms are temporary and can be managed effectively with the right strategies. By working with a healthcare provider and taking steps to manage symptoms, individuals can successfully withdraw from Effexor and regain control of their mental health. If you or a loved one is experiencing Effexor withdrawal, seek help from a healthcare provider as soon as possible.

Part 8: Additional Effexor Information The majority of people attempting Effexor withdrawal experience an antidepressant withdrawal syndrome. This is also known as Effexor discontinuation syndrome in the United States. In Europe it is called Effexor withdrawal side effects. The F.D.A. estimates 10% of those experiencing Effexor withdrawal will go back up on the Effexor because the withdrawal symptoms are too severe.

The most common and debilitating Effexor withdrawal side effect is called “brain zaps.” Brain zaps are described by people experiencing it as a; electrical jolt that tends to run from base of the neck up into their head. Another side effect that tends to run with brain zaps is a shiver, a feeling as your head is floating, dizziness, and/or a whirling sensation in the head.

These symptoms can come in waves or even be persistent. The good news: in 2002, our founder, Jim Harper, discovered the correct type of Omega 3 taken in the right quantity will eliminate these devastating head symptoms quickly. Usually within a couple of hours.

The body in a normal state uses the oil from our diet, specifically from omega 3 found in fish, to build and replenish the end point of areas in the brain that sends and receives electrical signals. We are using easy to understand terminology, so it is easy to understand. Let’s leave the technical jargon to physicians. These brain zaps have nothing to do with serotonin levels or other made-up reasons. It is simple really; our body works in a very natural way with how it uses amino acids, proteins, fats in food and all other diet items to maintain a balance. When you introduce any toxin that disrupts these processes the body reacts.

The most common Effexor Venlafaxene withdrawal symptoms reported include:

Flu like symptoms



Brain zaps




Increased suicidal ideation





Ringing in the ears




Mood swings

Please note: These are the most common Effexor withdrawal side effects but far from all potential Effexor withdrawal side effects.

There is a warning the FDA has put a black box warning on Effexor. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients (5.1) Closely monitor for clinical worsening and emergence of suicidal thoughts and behaviors

You may have been prescribed Effexor within a very short doctor visit. There was no investigation into other life factors, lab testing, or any conversation about what side effects might present. The failings of this approach may cause quite a burden on the patient.

Depression, insomnia, anxiety, fibromyalgia, and other symptoms that Effexor is often prescribed for might stem from; diminished vitamin D levels, overactive JNK gene, specific proteins that need to be silenced, dietary concerns and food allergies, mitochondrial dysfunction, neurotoxic accumulation, and many other reasons. A full physical from an understanding physician is ideal, before prescribing Effexor.

Do Your Symptoms Require Effexor?

The Road Back Program uses nutritional supplements to help with the Effexor withdrawal. Most people feel a very fast relief from the Effexor withdrawal once they begin taking the supplements and we feel the odds are high; if would have taken nutritional supplements like these before starting the Effexor you would have been prescribed the Effexor in the first place.

In 2007, Jim Harper was giving a speech to a group of psychiatrists in Ireland and during his talk he mentioned his mother just passed away 30 days ago. He went on to describe how he made sure to take his JNK Formula each day to help the body cope with the stress being put on it do to his loss. He went on to say, “The JNK Formula will not remove the emotional loss and how I feel but it will keep the body strong during my time to grieve.

“How Do You Survive Effexor Withdrawal?

Surviving Effexor withdrawal depends on what you do at this very moment. If you keep doing the same thing you have been doing and you are in a heavy Effexor withdrawal, nothing will change for the positive, that is a given.

If you decide to do the Effexor withdrawal as an inpatient in a drug rehab center DO NOT DO THE 9 DAY PLAN BECAUSE THAT WHAT INSURANCE ALLOWS. Over the past 22 years I have worked with far too many people who were sold on a rehab facility, stayed the 9 days because insurance would only pay for that amount of time. The unscrupulous facility took them off the Effexor in 9 days as they promised and by the time the person got off the airplane after their return home they were in full withdrawal. You can’t do an Effexor withdrawal in 9 days.

The Road Back Program can normally help you get back on your feet again, but the rehab facility approach of this type is not worth the price you will pay mentally and physically.

You will find a few other outpatient Effexor withdrawal programs on the internet now and Jim Harper is not aware of one that will cause you harm like the rehab facilities mentioned. However, every other program on the internet was trained by Jim Harper years ago and they are doing what Jim Harper and The Road Back did during that time frame. Almost 2 decades ago Jim Harper trained several physicians and good intentioned people how to get a patient off Effexor. Jim went into detail of the process and what nutritional supplements were used and why they were used. At that time of The Road Back the success rate was not as high as desired and over the following years Jim changed the formulas used with the supplements several times to use new information with DNA testing.

Long story short; you will likely wind up using an Effexor withdrawal approach The Road Back used in 2003, that was scrapped for something more successful. If you are currently in Effexor withdrawal, send Jim Harper an email and he will personally guide you through the process so you can get back on your feet quickly and have a very successful Effexor withdrawal. It does not matter if you have been on Effexor for 1 month or 20 years. Recovery can happen and the good part is it does not take more time because you have been taking Effexor for years. When Do Effexor Withdrawal Symptoms Start When Discontinuing / Quitting Effexor?

Effexor withdrawal usually begins between day 1 and day 3 of adjusting the Effexor. For some people this is not the case but eventually most everyone hits some dosage of the Effexor when reducing that jars them. Effexor withdrawal begins and they have no idea what they should do. Their physician does not know what to do. They wind up in a spiral downward and wind up on a new medication to try and stop the Effexor withdrawal. The best case is the additional drug does that, but you are now on 2 drugs instead of only Effexor.

What is Effexor?

Effexor is an antidepressant medication developed in the 1970s with FDA approval granted in 1991. This SSRI drug is prescribed in treating adult depressive disorders (MDD), panic disorder, obsessive compulsory disorders (OCD), social anxiety (SAD), post-traumatic stress disorders (PTSD), and premenstrual dysphoric disorder (PMDD).If you have anxiety before taking Effexor, or anxiety begins while taking Effexor, odds are the anxiety will continue to get worse. Effexor alters dopamine much like the antidepressant Effexor and anxiety is a byproduct of these two drugs.

What Is Effexor Used For?

Effexor is an antidepressant medication approved to treat adult MDD (major depressive disorder). The Black Box warning on the drug’s packaging mentions that the drug should not be prescribed to anyone under the age of 25, due to heightened risk of suicide. There is an exception to this for patients under the age of 25 who have been diagnosed with OCD (obsessive-compulsive disorder). Potential suicidality is associated with all Effexor and may be a concern leading to consider Effexor withdrawal, which is recommended to be done always under medical or caregiver monitoring.

Adult-only approved uses for the drug provided in a clinical or treatment setting include:

MDD: Major Depressive Disorder

PTSD: Post-traumatic stress disorder

PD: Panic disorder

SAD: Social anxiety disorder

OCD: Obsessive-compulsive disorder

PMDD: Premenstrual dysphoric disorder

Effexor Side Effects

The full list of Effexor side effects is quite staggering. In 2004, Jim Harper used the Freedom of Information Act to get the full list of Effexor side effects. Jim received the information, and it is 500 sheets of letter size paper, single space, a number 10 font size, 3 columns per page. In other words, thousands of known potential Effexor side effects were disclosed. Some of the other Effexor and Effexor withdrawal side effects:

Serotonin syndrome: A life-threatening condition requiring immediate medical care in a hospital emergency clinic or ICU. Symptoms to watch for include sudden fever, losing consciousness, inability to move or speak, copious sweating, dilated pupils, chills, tremors, convulsions, diarrhea, agitation, restlessness, racing heart, etc.

Suicidal thoughts (common) Suicide attempt (common)Hyperkinesis (muscle spasms, movement disorder) Worsened depression


Paranoia (rare)


Mania (common)




Teeth grinding

Akathisia (relentless internal restlessness and discomfort marked by repeated motions, pacing, rocking, etc., that can lead to suicidal thoughts as a means of relief)Tachycardia (racing heart, even when the body is at rest)



Burning, crawling feeling in the skin


Tics, sudden jerky movements, myoclonus

Emotional blunting

Behavioral apathy, SSRI-induced-indifference

Pain on urination or difficulty urinating

Cloudy urine


Sexual impairments, i.e., anorgasmia, inability to ejaculate, lowered libido Mood swings

Pain around the eyes or eye sockets


Bladder pain

Prickling skin sensation


Sensory disturbances


Depersonalization (common)


Nightmares (paroniria)




Weight gain

Some documented Effexor birth defects and injuries include:

PPHN or persistent pulmonary hypertension of the newborn, a heart and lung condition which can result in respiratory failure, decreased oxygen to the brain, and multiple organ injuries.

Congenital Heart Defects connected to Effexor and other SSRIs include ventricular septal defects and atrial septal defects, also referred to as “holes in the heart”, related to heart murmurs, suppressed appetite, breathing difficulties, tiredness, inadequate growth, etc.

Increased Risk of Autism has been extensively reported but evidence has not yet been considered conclusive enough for regulatory bodies to ban prescribing to pregnant women.

Increased Risk of Clubfoot connected to SSRIs during pregnancy as reported by NIMH, where exposure had the highest increase in clubfoot of all SSRIs.

Increased risk of atrial/ventricular defects and craniosynostosis was reported in a Canadian study from 1998 to 2010 and published in the June 2015 issue of the American Journal of Gynecology & Obstetrics.

Effexor Withdrawal, What to Expect

If using The Road Back Program, you should expect to feel a lot better within the first couple days of the program. If you do nothing, expect to continue to feel as you do now. Possibly worse as time goes on. The chance of feeling better if you do nothing is nil.

In 1999, The Road Back only had people taper the Effexor gradually and slowly. They still suffered. Around 50% could get off the Effexor but most went back on the Effexor because they continual Effexor withdrawal side effects would not diminish or go away.

We wish there was a better answer for you than the above but with working with over 19 million people over the last 22 years, the truth is the truth. No way to water it down to make it sound better.

Some may think it is just their depression returning but who would not feel depressed if they were still going through Effexor withdrawal months after stopping the Effexor. We can’t stress enough; what you do or do not do at this moment in time is critical for your future. Take your time if possible. If you have brain zaps go buy any omega 3 fish oil, even the wrong omega 3 fish oil will help somewhat. While you read this you may want to pause and go take a walk. Look at the trees, the sky or anything off in the distance. Getting your attention off your mind and body may do wonders. Keep this close to your heart; There is Hope and There is a Solution. We are speaking directly to YOU.A 30-day supply of the nutritional supplements will cost you around $80. If you feel it is worth around $80 to take a chance that all of this can go away in a couple of days, then take that chance. Over the past 22 years many have sent an email to Jim Harper and said they were not sure what to do about the Effexor withdrawal. Even after reading this information. The people that tried something else generally came back within a few months and were in worse shape than before. We do not want this to happen to you. But if so; Jim will still be here to assist.

Can Effexor Make Depression Worse?

Common sense answers this question. If depression is one side effect of taking Effexor, then Effexor can cause depression. You do stand a greater chance of Effexor causing depression during withdrawal than while simply taking the Effexor as prescribed. The depression during Effexor withdrawal can be due to the other Effexor withdrawal side effects you are experiencing. Who will not start to get depressed if you have anxiety from morning to night, can’t sleep and your head feels like it is on fire.

Effexor Aggression in Children

Children are more prone to aggression when taking Effexor than adults. It occurs in 10-20% of children taking any SSRI antidepressant. Two clinical trials performed by Pfizer, aggression was the most common reason noted for Effexor discontinuation.

Can You Get Addicted to Effexor?

Yes and no. This is where Effexor dependence is a matter of wording. Medically speaking in the United States Effexor is not addicting. In Europe it is viewed as addicting. The bottom line is; Once you take Effexor for 7 days the Effexor has made its way through your body. If your body no longer has the Effexor in its system, your body will react to the Effexor being gone. Much like a person that eats a lot a sweet every day. Your body will react when the sweet substance is not present. Call it addicting, as we would, call it a dependence as United States physicians will, it is what it is. If you do not provide the substance the body reacts, and you also have mental feelings that are not positive. We can get into the insulin discussion etc., but we are only talking about a substance being present and then not and the body and mind reacting in a negative manner.

What is the difference between Effexor and a Benzodiazepine?

Effexor is an SSRI medication, an antidepressant, used to treat depression and anxiety. Benzodiazepines are prescribed mainly for the treatment of anxiety and panic disorders but also prescribed off-label to treat depression.

These two types of drugs have different chemical components and were designed to work on different brain receptors and neurotransmitters, but some of their effects can be seen to overlap. Benzodiazepines are thought to mainly affect GABA transmission, which can slow the central nervous system to reduce anxiety, while Effexor is designed to block the reuptake of serotonin.

Benzodiazepines are known to be more prone to dependence/addiction than Effexor. While the withdrawal symptoms are similar between both drugs, Effexor’s half-life is 22-36 hours, and Benzodiazepines half-life is much lower. Benzodiazepines can have more severe complications if abruptly stopped, including seizures. For safe Benzodiazepine or Effexor withdrawal, either of these drugs must be slowly tapered to allow the central nervous system and neurochemistry to safely normalize.

Choosing to withdrawal from the Effexor first or the benzodiazepine first needs to be evaluated. Use Chapter 23, The Science to decide is part of that equation. Depending on the benzodiazepine you may be taking with the Effexor, if you reduce the Effexor first it may make you go into withdrawal on the benzodiazepine, even if you did not reduce the benzodiazepine.

How long does Effexor stay in your system after the last dosage?

Our founder, Jim Harper, made great strides with determining this question. Using his DNA testing company in 2004-2005, Jim conducted hundreds of DNA tests to determine how fast or slow medications took to metabolize. In roughly 34 percent of the population the Effexor can take as long as 48 hours to clear the body. In others, as little as 8 hours can occur for the Effexor to clear the body. Depending on other habits you may have, Effexor could clear faster or even take more time than the 48 hours. If you smoke cigarettes and stop smoking while taking Effexor, the Effexor dosage you are taking will decrease by 15%. On the other side of this, if you start smoking while taking Effexor, the Effexor dosage will act as though it is 15% higher than you think it is. This is because cigarettes induce an enzyme used to metabolize Effexor and anything using that same pathway will shoot though much faster. Caffeine restricts that same enzyme, so if you start or stop drinking coffee while taking Effexor you will either go into withdrawal or feel an overdose, even though you have not changed the Effexor dosage.

This is why The Road Back Program wants you to not change smoking habits or caffeine habits during the Effexor taper.

Can you overdose on Effexor?

Yes, it is definitely possible for Effexor poisoning to occur. A substantial Effexor overdose requires emergency medical intervention to prevent major health problems. This list of Effexor overdose symptoms would be the same as those Effexor side effects listed above, but more severe.

According to the National Institute of Health (NIH), the use of intravenous benzodiazepines is sometimes required during Effexor overdose to prevent seizures. Extra cooling measures must be used to reduce hyperthermia, always under the direction of EMT or other medical staff attending to the patient.

Treatment for Effexor Withdrawal

Effexor has become one of the most frequently prescribed antidepressants in the US. Of equal importance is that depressive disorders have become one of the most frequently diagnosed conditions. These two facts together underscore two important steps toward improved health:

Providing safe treatment programs for those who have decided on Effexor withdrawal and offering drug-free options to regain natural mental health without the need for prescription medications.

The Road Back Program was described by Dr. Hyla Cass M.D. in this way:

Here’s an essential handbook on how to safely and more easily wean yourself (under medical supervision) off the heavily over-prescribed psychotropic medications. I have used the program with my patients, and it works! “Hyla Cass M.D. Author of Supplement Your Prescription

Send an email to Jim Harper by using the Contact link on the top of this page or read How to Get Off Psychoactive Drugs Safely by Jim Harper and follow the program for Effexor withdrawal.

Why Jim put his entire book on our website for free is so you can instantly read the material and start this process if you are ready now.

One last thing Jim asked us to provide at the bottom of each page of Effexor descriptions:

There is Hope and There is a Solution

1. Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications

Studies on psychotropic medications decrease, discontinuation, or switch have uncovered withdrawal syndromes. The present overview aimed at analyzing the literature to illustrate withdrawal after decrease, discontinuation, or switch of psychotropic medications based on the drug class (i.e., benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonists, antidepressants, ketamine, antipsychotics, lithium, mood stabilizers) according to the diagnostic criteria of Chouinard and Chouinard [Psychother Psychosom. 2015;84(2):63-71], which encompass new withdrawal symptoms, rebound symptoms, and persistent post-withdrawal disorders. All these drugs may induce withdrawal syndromes and rebound upon discontinuation, even with slow tapering. However, only selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, and antipsychotics were consistently also associated with persistent post-withdrawal disorders and potential high severity of symptoms, including alterations of clinical course, whereas the distress associated with benzodiazepines discontinuation appears to be short-lived. As a result, the common belief that benzodiazepines should be substituted by medications that cause less dependence such as antidepressants and antipsychotics runs counter the available literature. Ketamine, and probably its derivatives, may be classified as at high risk for dependence and addiction. Because of the lag phase that has taken place between the introduction of a drug into the market and the description of withdrawal symptoms, caution is needed with the use of newer antidepressants and antipsychotics. Within medication classes, alprazolam, lorazepam, triazolam, paroxetine, venlafaxine, fluphenazine, perphenazine, clozapine, and quetiapine are more likely to induce withdrawal. The likelihood of withdrawal manifestations that may be severe and persistent should thus be taken into account in clinical practice and also in children and adolescents.

Keywords: Antidepressant; Antipsychotic; Benzodiazepine; Discontinuation; Lithium; Mood stabilizers; Selective serotonin reuptake inhibitor; Serotonin noradrenaline reuptake inhibitor; Tolerance; Withdrawal.

2. Antidepressant Withdrawal and Rebound Phenomena

Background: Antidepressants are among the most commonly prescribed drugs worldwide. They are often discontinued, frequently without the knowledge of the prescribing physician. It is, therefore, important for physicians to be aware of the withdrawal and rebound phenomena that may arise, in order to prevent these phenomena, treat them when necessary, and counsel patients appropriately.

Methods: This review is based on a comprehensive, structured literature search on antidepressant withdrawal phenomena that we carried out in the CENTRAL, PubMed (Medline), and Embase databases. We classified the relevant publications and reports by their methodological quality.

Results: Out of a total of 2287 hits, there were 40 controlled trials, 38 cohort studies and retrospective analyses, and 271 case reports that met the inclusion criteria. Withdrawal manifestations are usually mild and self-limiting; common ones include dizziness, headache, sleep disturbances, and mood swings. More serious or pro- longed manifestations rarely arise. There is an increased risk with MAO inhibitors, tricyclic antidepressants, venlafaxine, and paroxetine; on the other hand, for agome- latine and fluoxetine, abrupt discontinuation seems to be unproblematic. There is also some evidence of rebound phenomena, i.e., of higher relapse rates or especially severe relapses of depression after the discontinuation of an anti- depressant.

Conclusion: A robust evidence base now indicates that there can be acute with- drawal phenomena when antidepressants are discontinued. Putative rebound phenomena have not been adequately studied to date. It is recommended that antidepressants should be tapered off over a period of more than four weeks.

3. Withdrawal Symptoms after Serotonin-Noradrenaline Reuptake Inhibitor Discontinuation: Systematic Review

Background: Serotonin-noradrenaline reuptake inhibitors (SNRI) are widely used in medical practice. Their discontinuation has been associated with a wide range of symptoms. The aim of this paper is to identify the occurrence, frequency, and features of withdrawal symptoms after SNRI discontinuation.

Methods: PRISMA guidelines were followed to conduct a systematic review. Electronic databases included PubMed, the Cochrane Library, Web of Science, and MEDLINE from the inception of each database to June 2017. Titles, abstracts, and topics were searched using a combination of the following terms: “duloxetine” OR “venlafaxine” OR “desvenlafaxine” OR “milnacipran” OR “levomilnacipran” OR “SNRI” OR “second generation antidepressant” OR “serotonin norepinephrine reuptake inhibitor” AND “discontinuation” OR “withdrawal” OR “rebound.” Only published trials in the English language were included.

Results: Sixty-one reports met the criteria for inclusion. There were 22 double-blind randomized controlled trials, 6 studies where patients were treated in an open fashion and then randomized to a double-blind controlled phase, 8 open trials, 1 prospective naturalistic study, 1 retrospective study, and 23 case reports. Withdrawal symptoms occurred after discontinuation of any type of SNRI. The prevalence of withdrawal symptoms varied across reports and appeared to be higher with venlafaxine. Symptoms typically ensued within a few days from discontinuation and lasted a few weeks, also with gradual tapering. Late onset and/or a longer persistence of disturbances occurred as well.

Conclusions: Clinicians need to add SNRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with other types of psychotropic drugs. The results of this study challenge the use of SNRI as first-line treatment for mood and anxiety disorders.

Keywords: Adverse events; Antidepressant drugs; Desvenlafaxine; Discontinuation syndrome; Duloxetine; Levomilnacipran; Milnacipran; Serotonin-noradrenaline reuptake inhibitors; Venlafaxine; Withdrawal symptoms.

4. Withdrawal Syndrome Following Discontinuation of 28 Antidepressants: Pharmacovigilance Analysis of 31,688 Reports from the WHO Spontaneous Reporting Database

Introduction: Evidence is lacking on withdrawal syndrome related to individual antidepressants and relevant risk factors for severe reactions.

Objective: To ascertain whether antidepressants are associated with an increased reporting of withdrawal syndrome as compared with other medications, and to investigate risk factors for severe reactions.

Methods: This is a case/non-case pharmacovigilance study, based on the VigiBase®, the WHO global database of individual case safety reports of suspected adverse drug reactions. We performed a disproportionality analysis of reports of antidepressant-related withdrawal syndrome (calculating reporting odds ratio [ROR] and Bayesian information component [IC]). We compared antidepressants to all other drugs, to buprenorphine (positive control), and to each other within each class of antidepressants (selective serotonin reuptake inhibitors [SSRIs], tricyclics and other antidepressants). Antidepressants with significant disproportionate reporting were ranked in terms of clinical priority. Serious versus non-serious reactions were compared.

Results: There were 31,688 reports of antidepressant-related withdrawal syndrome were found. A disproportionate reporting was detected for 23 antidepressants. The estimated ROR for antidepressants altogether, compared to all other drugs, was 14.26 (95% CI 14.08-14.45), 17.01 for other antidepressants (95% CI 16.73-17.29), 13.65 for SSRIs (95% CI 13.41-13.90) and 2.8 for tricyclics (95% CI 2.59-3.02). Based on clinical priority ranking, the strongest disproportionate reporting was found for paroxetine, duloxetine, venlafaxine and desvenlafaxine, being comparable to buprenorphine. Withdrawal syndrome was reported as severe more often in males, adolescents, persons in polypharmacy, and with a longer antidepressant treatment duration (p < 0.05).

Conclusions: Antidepressants are associated with an increased reporting of withdrawal syndrome compared with other drug classes. When prescribing and discontinuing antidepressants, clinicians should be aware of the potentially different proclivity of withdrawal syndrome across individual antidepressants, and the liability to experience more severe withdrawal symptoms in relation to specific patient characteristics.

5. Antidepressant withdrawal reactions

Antidepressants can cause a variety of withdrawal reactions, starting within a few days to a few weeks of ceasing the drug and persisting for days to weeks. Both tricyclic antidepressants and selective serotonin reuptake inhibitors cause similar syndromes, most commonly characterized by gastrointestinal or somatic distress, sleep disturbances, mood fluctuations and movement disorders. Most symptoms related to tricyclic antidepressant withdrawal are believed to be caused by rebound excess of cholinergic activity after prolonged anticholinergic effect on cholinergic receptors. (This situation is analogous to the adrenergic rebound that occurs after beta-blocker withdrawal.) Treatment involves restarting the antidepressant and tapering it more slowly. Alternatively, tricyclic antidepressant withdrawal symptoms often respond to anticholinergics, such as atropine or benztropine mesylate. Three case reports of antidepressant withdrawal are presented, including one featuring akathisia (motor restlessness) related to withdrawal of venlafaxine.

6. Antidepressants for people with epilepsy and depression

Background: Depressive disorders are the most common psychiatric comorbidity in people with epilepsy, affecting around one-third, with a significant negative impact on quality of life. There is concern that people may not be receiving appropriate treatment for their depression because of uncertainty regarding which antidepressant or class works best, and the perceived risk of exacerbating seizures. This review aimed to address these issues, and inform clinical practice and future research. This is an updated version of the original Cochrane Review published in Issue 12, 2014.

Objectives: To evaluate the efficacy and safety of antidepressants in treating depressive symptoms and the effect on seizure recurrence, in people with epilepsy and depression.

Search methods: For this update, we searched CRS Web, MEDLINE, SCOPUS, PsycINFO, and ClinicalTrials.gov (February 2021). We searched the World Health Organization Clinical Trials Registry in October 2019, but were unable to update it because it was inaccessible. There were no language restrictions.

Selection criteria: We included randomised controlled trials (RCTs) and prospective non-randomised studies of interventions (NRSIs), investigating children or adults with epilepsy, who were treated with an antidepressant and compared to placebo, comparative antidepressant, psychotherapy, or no treatment for depressive symptoms. DATA COLLECTION AND ANALYSIS: The primary outcomes were changes in depression scores (proportion with a greater than 50% improvement, mean difference, and proportion who achieved complete remission) and change in seizure frequency (mean difference, proportion with a seizure recurrence, or episode of status epilepticus). Secondary outcomes included the number of participants who withdrew from the study and reasons for withdrawal, quality of life, cognitive functioning, and adverse events. Two review authors independently extracted data for each included study. We then cross-checked the data extraction. We assessed risk of bias using the Cochrane tool for RCTs, and the ROBINS-I for NRSIs. We presented binary outcomes as risk ratios (RRs) with 95% confidence intervals (CIs) or 99% CIs for specific adverse events. We presented continuous outcomes as standardised mean differences (SMDs) with 95% CIs, and mean differences (MDs) with 95% CIs. MAIN RESULTS: We included 10 studies in the review (four RCTs and six NRSIs), with 626 participants with epilepsy and depression, examining the effects of antidepressants. One RCT was a multi-centre study comparing an antidepressant with cognitive behavioural therapy (CBT). The other three RCTs were single-centre studies comparing an antidepressant with an active control, placebo, or no treatment. The NRSIs reported on outcomes mainly in participants with focal epilepsy before and after treatment for depression with a selective serotonin reuptake inhibitor (SSRI); one NRSI compared SSRIs to CBT. We rated one RCT at low risk of bias, three RCTs at unclear risk of bias, and all six NRSIs at serious risk of bias. We were unable to conduct any meta-analysis of RCT data due to heterogeneity of treatment comparisons. We judged the certainty of evidence to be moderate to very low across comparisons, because single studies contributed limited outcome data, and because of risk of bias, particularly for NRSIs, which did not adjust for confounding variables. More than 50% improvement in depressive symptoms ranged from 43% to 82% in RCTs, and from 24% to 97% in NRSIs, depending on the antidepressant given. Venlafaxine improved depressive symptoms by more than 50% compared to no treatment (mean difference (MD) -7.59 (95% confidence interval (CI) -11.52 to -3.66; 1 study, 64 participants; low-certainty evidence); the results between other comparisons were inconclusive. Two studies comparing SSRIs to CBT reported inconclusive results for the proportion of participants who achieved complete remission of depressive symptoms. Seizure frequency data did not suggest an increased risk of seizures with antidepressants compared to control treatments or baseline. Two studies measured quality of life; antidepressants did not appear to improve quality of life over control. No studies reported on cognitive functioning. Two RCTs and one NRSI reported comparative data on adverse events; antidepressants did not appear to increase the severity or number of adverse events compared to controls. The NSRIs reported higher rates of withdrawals due to adverse events than lack of efficacy. Reported adverse events for antidepressants included nausea, dizziness, sedation, headache, gastrointestinal disturbance, insomnia, and sexual dysfunction. AUTHORS’ CONCLUSIONS: Existing evidence on the effectiveness of antidepressants in treating depressive symptoms associated with epilepsy is still very limited. Rates of response to antidepressants were highly variable. There is low certainty evidence from one small RCT (64 participants) that venlafaxine may improve depressive symptoms more than no treatment; this evidence is limited to treatment between 8 and 16 weeks, and does not inform longer-term effects. Moderate to low evidence suggests neither an increase nor exacerbation of seizures with SSRIs. There are no available comparative data to inform the choice of antidepressant drug or classes of drug for efficacy or safety for treating people with epilepsy and depression. RCTs of antidepressants utilising interventions from other treatment classes besides SSRIs, in large samples of patients with epilepsy and depression, are needed to better inform treatment policy. Future studies should assess interventions across a longer treatment duration to account for delayed onset of action, sustainability of treatment responses, and to provide a better understanding of the impact on seizure control.

7. Venlafaxine

Infants receive venlafaxine and its active metabolite in breastmilk, and the metabolite of the drug can be found in the plasma of most breastfed infants; however, concurrent side effects have rarely been reported. Some experts feel that venlafaxine is not recommended during nursing,[1] but a safety scoring system finds venlafaxine use to be possible during breastfeeding.[2] Breastfed infants, especially newborn or preterm infants, should be monitored for excessive sedation and adequate weight gain if this drug is used during lactation, possibly including measurement of serum levels of desvenlafaxine (O-desmethylvenlafaxine), to rule out toxicity if there is a concern. Bruxism has also been reported in one infant. However, newborn infants of mothers who took the drug during pregnancy may experience poor neonatal adaptation syndrome as seen with other antidepressants such as SSRIs or SNRIs. Use of venlafaxine during breastfeeding has been proposed as a method of mitigating infant venlafaxine withdrawal symptoms,[3,4] but this has not been rigorously demonstrated.

8. Venlafaxine withdrawal syndrome

Dual-action antidepressants serotonin-norepinephrine reuptake inhibitors (SRNIs) are widely used to treat depression. Owing to its efficiency and safety, venlafaxine holds a prominent place in this group of depressants. Abrupt venlafaxine discontinuation involves a high risk of withdrawal syndrome. Mechanism of its development is similar to that of selective serotonin reuptake inhibitors (SSRIs), but of higher intensity. Venlafaxine withdrawal symptoms may include several somatic symptoms as well as several psychiatric symptoms. In some cases, symptoms may look like a stroke. A treatment option is re-inclusion of venlafaxine or a SSRI antidepressant. The paper presents the case of a 70-year-old patient who discontinued of her own accord to take venlafaxine, which she had been taking regularly at a daily dose of 225 mg for more than a year. A few hours after taking the last dose, withdrawal syndrome occurred with severe symptoms resembling a stroke. The patient was examined by a neurologist and the CT and laboratory parameters showed no irregularities. Diagnosis was made after psychiatric observation. Venlafaxine, 150 mg per day, was prescribed, the symptoms disappeared relatively quickly, and the patient fully recovered. Withdrawal syndrome is a real risk for each venlafaxine treated patient. The possibility of its occurrence should be always kept in mind and patients should be timely informed about it. In this way, the risk of venlafaxine withdraw syndrome could be reduced, unnecessary stress to patients prevented and the costs of medical treatment lowered.

9. Withdrawal symptoms of antidepressants

Withdrawal symptoms are encountered with both the classical anti-depressants, i.e. the tricyclic antidepressants and monoamineoxidase inhibitors, the modern antidepressants, i.e. the selective serotonin re-uptake inhibitors, and the new antidepressants such as venlafaxine and mirtazapine. The symptoms that are reported following the withdrawal of these drugs can be classified into 8 groups: influenza-like symptoms, psychic symptoms, gastrointestinal symptoms, sleep disorders, equilibrium disorders, sensory disturbances, extrapyramidal symptoms and other symptoms. It is characteristic of these symptoms that they appear 1-4 days after reduction of the dose or the last administration of the drug. They may also appear in the infants of mothers who used an antidepressant during the last phase of the pregnancy. It is important that the patient be informed accurately and carefully at the start and termination of any treatment with an antidepressant. In order to prevent withdrawal symptoms, it is advisable to reduce the dosage slowly if possible when the treatment is to be terminated.

10. Serotonergic anti-depressants and ethanol withdrawal syndrome: a review

Aim: To review laboratory findings on the effects of anti-depressant agents that interact with the serotonergic system on signs of ethanol withdrawal syndrome in rats.

Method: Adult Wistar rats received a modified liquid diet to produce ethanol dependence. Signs of ethanol withdrawal, locomotor hyperactivity, stereotyped behaviour, tremor, wet dog shakes, agitation, and audiogenic seizures, were evaluated for the first 6 h of ethanol withdrawal. The effects of the anti-depressants fluoxetine, venlafaxine, escitalopram, tianeptine, and extract of Hypericum perforatum (St. John’s wort) (HPE) were examined.

Results: Some beneficial effects of fluoxetine, tianeptine, HPE, escitalopram and venlafaxine on ethanol withdrawal signs were observed, ranked as follows: fluoxetine = tianeptine > HPE > escitalopram > venlafaxine.

Conclusions: Tianeptine and fluoxetine seem to be potent pharmacologically active agents on ethanol withdrawal syndrome in rats. Thus, these anti-depressants may be useful in treatment of ethanol withdrawal syndrome in patients with alcoholism. In addition to serotonergic effects, interactions with nitrergic, glutamatergic, and adenosinergic systems may also provide a significant contribution to the beneficial effects of these drugs on ethanol withdrawal syndrome.