SSRI discontinuation syndrome

SSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a condition that can occur during or following the interruption, lowering of dose or discontinuation of regular SSRI or SNRI antidepressant drug usage. The condition often begins between 24 hours to one week after reduction in dosage or complete discontinuation, depending on the elimination half-life of the drug. The prescribing labels of SSRIs acknowledge the possibility of "intolerable" discontinuation reactions, and some patients have extreme difficulty discontinuing use from SSRI drugs.

Indicators
The indicators of SSRI discontinuation syndrome are the following:


 * Interruption, cessation, or reduction of dosage in an SSRI treatment that has lasted four or more weeks.
 * Symptoms interfere with normal social, occupational, or other functioning.
 * Symptoms are not due to another medical condition, drug use, or discontinuation.
 * Symptoms are not due to a relapse of the condition for which the SSRI was originally prescribed.

History
The first report of withdrawal symptoms occurring after SSRI discontinuation was for fluvoxamine (brand names Luvox [US], Faverin [UK]) in 1992. The Committee on Safety of Medicines in the United Kingdom reported withdrawal symptoms involving paroxetine (Paxil, Seroxat) in 1993, and the American Journal of Psychiatry revealed the same for sertraline (Zoloft, Lustral) the following year.

List of SSRIs
Many drugs in this class are familiar in the USA through advertising, including the following: (Trade names in parentheses)


 * citalopram (Celexa, Cipramil, Emocal, Sepram, Seropram)
 * escitalopram (Lexapro, Cipralex, Esertia)
 * fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR))
 * paroxetine (Paxil, Seroxat, Aropax, Deroxat, Paroxat)
 * sertraline (Zoloft, Lustral, Serlain)
 * venlafaxine (Effexor)
 * duloxetine (Cymbalta)
 * dapoxetine (no known trade name)
 * fluvoxamine (Luvox, Faverin)

Venlafaxine and duloxetine are both members of the SNRI class of antidepressant medication. SNRIs (serotonin-norepinephrine reuptake inhibitors) work on the norepinephrine and serotonin neurotransmitters.

Note that trazodone is not a typical member of the SSRIs - while it is a serotonin reuptake inhibitor, it is believed that its anti-depressant properties may be due to some of its other pharmacodynamic properties rather than its effect on serotonin reuptake. That said, it does still share many properties of the typical SSRIs, especially the possibility of a 'discontinuation syndrome'.

Symptoms
Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated SSRIs. Just because a side effect is stated here, it does not mean that all people using one of these medicines will experience that or any side effect. The discontinuation (specifically when abrupt) of antidepressants can result in a syndrome of adverse events, including somatic, mood and psychomotor reactions.
 * Dry mouth
 * Headache
 * Insomnia
 * Somnolence
 * Dizziness, or Orthostatic hypotension
 * Fatigue
 * Cataplexy
 * Increased sweating
 * Decreased appetite and weight loss
 * Intraocular pressure or blurred vision
 * Paresthesia
 * Disturbances of the gut, such as nausea, constipation, diarrhea, indigestion, vomiting
 * Tremor
 * Nightmares
 * Akathisia, (anxiety, nervousness, agitation, suicidal thoughts)
 * Palpitations
 * Decreased sex drive or difficulty achieving orgasm
 * Impotence or delayed ejaculation
 * Hot flashes
 * Taste disturbances
 * Dysphoria
 * Difficulty passing urine
 * Increase in blood pressure or heart rate
 * Cold hands or feet
 * Jaundice
 * Inflammation of the liver
 * Depersonalization
 * Myoclonus (involuntary muscle twitching)
 * Tinnitus
 * Extreme yawning, feeling of lack of Oxygen
 * Extreme sensitivity to fluorescent light

"Brain zaps" and "electric shock sensations"
"Brain zaps", also known as "brain shocks" or "brain shivers", are a fairly common withdrawal symptom experienced during discontinuation (or reduction in dose) of SSRI and SNRI antidepressant drugs. The symptom is described as brief but repeated electric shock-like sensations in the brain and head.

Paresthesia and "electric shock" sensations are clinical terms used to describe this symptom, though paresthesia by definition is clinically incorrect. The "brain zap" effect appears to be nearly unique to serotonergic antidepressant drug formulations which have an extremely short elimination half-life in the body; that is, they are more quickly metabolized by the liver and leave the general circulation faster than longer half-life antidepressants such as fluoxetine (Prozac). This attribute of abruptness leaves the brain a relatively short time to adapt to a major neurochemical change when medication ceases, and the symptoms may be caused by the brain's attempt at readjustment. There is yet no evidence that these "zaps" present any danger to the patient experiencing them however they can be very disconcerting to patients whom have no prior warning or knowledge of them.

Post SSRI Sexual Dysfunction
Post SSRI Sexual Dysfunction (PSSD) is an iatrogenic type of sexual dysfunction caused directly by the previous use of SSRIs. While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs. It may represent a specific subtype of SSRI discontinuation syndrome.

One or more of the following sexual symptoms persist or begin after the discontinuation of SSRIs:


 * Decreased or absent libido
 * Impotence or reduced vaginal lubrication
 * Difficulty initiating or maintaining an erection or becoming aroused
 * Persistent sexual arousal syndrome despite absence of desire
 * Muted, delayed or absent orgasm (anorgasmia)
 * Reduced or no experience of pleasure during orgasm (ejaculatory anhedonia)
 * Premature ejaculation
 * Weakened penile or clitoral sensitivity
 * Genital anesthesia
 * Loss or decreased response to sexual stimuli
 * Reduced semen volume
 * Priapism

Lack of diagnostic criteria
Although SSRIs are widely used and generally considered safe, an abrupt cessation, or rapid tapering of SSRI use may result in a discontinuation syndrome that can mimic serious illness and can be distressing and uncomfortable. Several pharmacokinetic and pharmacodynamic factors influence the frequency and onset of these symptoms. When allowed to run its course, the syndrome duration is variable (usually one to several weeks) and ranges from mild-moderate intensity in most patients, to extremely distressing in a smaller number of patients who may have side effects for months, and in extremely rare cases permanently.

With the lack of a definition based on consensus criteria for the syndrome, a discontinuation panel met in Phoenix, Arizona in 1997 and purported that:


 * "SSRI discontinuation symptoms... may emerge when an SSRI is abruptly discontinued, when doses are missed, and less frequently, during dosage reduction. In addition, the symptoms are not attributable to any other cause and can be reversed when the original agent is reinstituted, or one that is pharmacologically similar is substituted. SSRI discontinuation symptoms, in most cases, may be minimized by slowly tapering antidepressant therapy, but there have been several case reports where symptoms occurred consistently even through repeated attempts to taper therapy. Physical symptoms include problems with balance, gastrointestinal and flu-like symptoms, and sensory and sleep disturbances. Psychological symptoms include anxiety and/or agitation, crying spells, and irritability."

A 2000 study at the Department of Psychiatry at Dalhousie University in Halifax, Nova Scotia constructed a diagonistic criteria for SSRI discontinuation syndrome. These criteria are 2 or more of the following symptoms developing within 1 to 7 days of discontinuation or reduction in dosage of an SSRI after at least 1 month's use, when these symptoms cause clinically significant distress or impairment and are not due to a general medical condition or recurrence of a mental disorder: dizziness, light-headedness, vertigo or feeling faint; shock-like sensations or paresthesia; anxiety; diarrhea; fatigue; gait instability; headache; insomnia; irritability; nausea or emesis; tremor; and visual disturbances.

Due to a lack of peer reviewed diagnostic criteria many physicians, unaware of the potential severity of discontinuation syndrome, do not get informed consent at the time of initial prescription from the patient (though patients in clinical trials do), so this syndrome can be an unexpected barrier to patients attempting to discontinue the drug. In addition, warnings to patients not to stop taking the drug without doctor's approval, while indicated, may lead to a reluctance to discontinue SSRI therapy in patients who need not take the drugs long-term.

Definition of withdrawal
The term withdrawal has been used in the past for SSRI discontinuation syndrome; however, discontinuation symptoms and classical drug withdrawal are different. Thus, the use of proper terminology when discussing this phenomenon is still ambiguous. SSRIs are not addictive in the conventional medical use of the word (i.e. animals given free access to the drug do not actively seek it out and do not seek to increase the dose), but suddenly discontinuing their use is known to produce both somatic and psychological symptoms, as described by researchers.

Critics argue that the pharmaceutical industry has a vested interest in creating a distinction between addiction to recreational or illegal drugs and dependence on antidepressants. Arguments against the use of the term 'withdrawal' are primarily predicated on not frightening patients or alienating potential customers who may or may not need the medication. According to the consensus definition by the American Academy of Pain Medicine, withdrawal is a symptom of "Physical Dependence", not of "Addiction" and thus arguments against SSRIs being "addictive" do not clearly make the use of the term "withdrawal" inappropriate to the symptoms caused by ceasing an SSRI.

Mechanism
Antidepressant withdrawal effects do not indicate addiction in the strict medical sense, but are rather the results of the brain attempting to reach neurochemical stability after an abrupt change. The exact mechanism of SSRI discontinuation syndrome is unknown, and may be a variety of factors. Continuing research on discontinuation/withdrawal syndrome has attributed SSRI discontinuation syndrome to electrophysiological changes in the brain (particularly on the 5-HT receptor), and electrophysiological changes in the body (nerve growth factor) in the absence of the SSRI, as well as dopamine dependency, and an over-excited immune system.

The central nervous system (CNS) adapts to the presence of psychoactive drugs. Such adaptation commonly involves the readjustment of neuroreceptors to compensate for the acute pharmacological action of the medication. Desired drug effects may be mediated by such compensatory changes which may explain the delayed onset of therapeutic effect of antidepressants. This adaptation theory also explains why withdrawal symptoms and signs can occur on the discontinuation of such medications as clearance of drug can occur at a rate faster than the brain can readjust to the absence of medication. Hence, pharmacodynamic and pharmacokinetic factors contribute to the risk of a withdrawal syndrome. Pharmacodynamic factors explain why withdrawal syndromes are often a class issue and why the administration of a drug in the same class often relieves withdrawal symptoms. Formal studies have not characterized the relative risk.

One theory purported by the Brain Imaging Center, McLean Hospital, Harvard Medical School, states that SSRI discontinuation syndrome is associated with a rostral anterior cingulate Cho/Cre metabolite ratio decrease that may reflect dynamics of rostral anterior cingulate cortex (ACC) function.

The ACC appears to play a role in a wide variety of autonomic functions, such as regulating heart rate and blood pressure, and is vital to cognitive functions, such as reward anticipation, decision-making, empathy, and emotion. Neuroscientists indicate the dorsal anterior cingulate cortex is primarily related to rational cognition while the ventral is more related to emotional cognition.

A separate study at the McLean Hospital and Department of Psychiatry, Harvard Medical School, demonstrated that changes in regional central blood volume (CBV) of left prefrontal cortex and left caudate nucleus correlate with the emergence of discontinuation symptoms and increased Hamilton Depression Rating Scale (HDRS) after interruption of paroxetine treatment. The findings supported the hypothesis that brain regions implicated in depression, with extensive serotonergic innervation, would exhibit changes in activity associated with emergence of symptoms following drug discontinuation. Cerebral blood volume (CBV) maps were obtained via dynamic susceptibility functional magnetic resonance imaging (fMRI).

There is speculation concerning the possibility of a temporary deficiency of synaptic serotonin with abrupt withdrawal of an SSRI. This deficiency is compounded by the fact that down-regulated receptors will remain in their relatively hypoactive state for days to weeks. This is believed to result in antidepressant discontinuation syndrome directly or indirectly via downstream effects on other neurotransmitter systems (e.g., norepinephrine, dopamine, and g-aminobutyric acid) implicated in depressive and anxiety disorders.

Another possible mechanism is by inhibition of dopaminergic neurotransmission.

Prevention and treatment
Patients should be advised of the elimination half-life times on their specific medication, and patients should be aware if changing from a long half-life medication such as fluoxetine, to a shorter one, that taking their dose regularly becomes much more important. Patients taking fluoxetine can often miss several doses without noticing any discomfort, but the shorter halflife of other SSRIs such as venlafaxine, paroxetine, duloxetine, escitalopram oxalate and sertraline (ranging approximately 10 hours) means that a single missed dose may cause withdrawal symptoms.

The condition may be avoided by either recommencing the original, and/or lesser dose of the SSRI (or a similar SSRI), or slowly reducing (titrating) the dosage over several weeks or months. While slowly reducing the dosage does not guarantee that a patient will not experience the discontinuation syndrome, it is considered a safer method than abrupt discontinuation.

Treatment is dependent on the severity of the discontinuation reaction and whether or not further antidepressant treatment is warranted. In cases where further antidepressant treatment is required then the only step required is restarting the antidepressant; this is usually the case following patient noncompliance with the drug. If antidepressants are no longer required, treatment depends on symptom severity. Mild reactions may only require reassurance. Moderate cases may require symptom management, for example benzodiazepines can be used for insomnia. If symptoms are severe, or do not respond to symptom management, the antidepressant can be reinstated and then withdrawn more cautiously.

For severe withdrawals, many doctors have patients taper their medication no more than 5% per week, as to avoid a drastic drop in serotonergic activity. This slow taper can be done either by purchasing oral suspension versions of the drug (if available), cutting pills, or dissolving capsules of the medication in orange juice.

Tapering regimen
A tapering regimen is not provided in manufacturers' package inserts. The optimum tapering regimen for each agent has yet to be determined by comparative clinical trials. From a review of the case reports (MEDLINE search from 1982 to May 1997), the following tapering schedules presented are suggested.

Suggested SSRI and SSNRI Tapering Schedule Fluoxetine:    Reduce by  5 mg every two weeks until dose is  5 mg/day, then  2.5 mg/day every two weeks Fluvoxamine, Sertraline, Venlafaxine:    Reduce by 25 mg every two weeks until dose is 25 mg/day, then 12.5 mg/day every two weeks Paroxetine:    Reduce by 10 mg every two weeks until dose is 10 mg/day, then  5.0 mg/day every two weeks

Example Case: A patient is receiving 20 mg/day of fluoxetine. Upon discontinuation patient experiences symptoms of SSRI withdrawal. Resume fluoxetine at a dose of 20 mg/day until symptoms abate. Then decrease the dose by 5 mg to 15 mg/day for two weeks. If the patient tolerates the lower dose without withdrawal symptoms decrease the dose to 10 mg/day for two weeks. Continue the taper according to the above schedule.

Persistent adverse effects
Recent case reports describe four young men and women who experienced serious sexual dysfunction that continued to be symptomatic despite medication discontinuation years previously.

Long term withdrawal syndromes outside of sexual dysfunction from SSRIs are not well documented, but reports are starting to be published. Symptoms can persist for months and include agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, crying spells or mood lability, overactivity or hyperactivity, depersonalization, decreased concentration, slowed thinking, confusion and memory/concentration difficulties. For some patients in this condition, restarting the drug can cause intolerable side effects, meaning these symptoms have to be endured until they eventually subside.

The persisting adverse effects seen with SSRI discontinuation may be a part of Post Acute Withdrawal Syndrome (PAWS). PAWS is a set of impairments that occur after withdrawal from addictive substances. The condition lasts from six to eighteen months after the last use and is marked by a fluctuating but incrementally improving course. It has importance to the recovering patient's ability to benefit from recovery, treatment, function effectively on the job, interact with family and friends, and regain emotional health. Most individuals find the first six months to be the most PAWS impacted with decreasing severity over the next six-month period. By the end of one year, most persons have returned to their respective levels of functioning.

In the addict, symptoms appear approximately seven to fourteen days into abstinence, after stabilization from the acute withdrawal. Post-acute withdrawal is a bio-psycho-social syndrome. It results from the combination of damage to the nervous system caused by drugs and the psychosocial stress of coping with life without the drug that has been discontinued. The symptoms of PAWS typically grow to peak intensity over three to six months after abstinence begins. The damage is usually reversible, meaning the major symptoms go away in time if proper treatment is received. Symptoms most often seen in PAWS are emotional lability, psychomotor problems (cognitive impairment, movement disorder, dizziness), sleep disturbances, and anxiety.

Discontinuation of SNRIs
SNRIs affect both reuptake inhibition of serotonin and norepinephrine. They are considered the strongest of the SSRI family of drugs. The two mostly widely prescribed SNRIs are venlafaxine and duloxetine.

Discontinuation of Venlafaxine
Sudden discontinuation of venlafaxine has a high risk of causing potentially severe withdrawal symptoms. Even missing a single dose can cause symptoms of withdrawal. The high risk of withdrawal symptoms reflect venlafaxine's short half-life as well as its effect as a dual uptake inhibitor. Discontinuations have a tendency to be significantly stronger than the withdrawal effects of other antidepressants including the tricyclic antidepressants, but are similar in nature to those of SSRIs with short half-life such as paroxetine.

Symptoms of discontinuation are similar to other antidepressants including irritability, restlessness, headache, nausea, fatigue, excessive sweating, dysphoria, tremor, vertigo, irregularities in blood pressure, dizziness, visual and auditory hallucinations, feelings of abdominal distension, and paresthesia. Other non-specific mental symptoms may include impaired concentration, bizarre dreams, delirium, cataplexy, agitation, and worsening of depressive symptoms.

Electric shock sensations have also been reported with many patients describing the symptoms as "brain zaps". It has been suggested the sensations may represent an alteration of neuronal activity in the central nervous system.

Studies by Wyeth-Ayerst, the maker of venlafaxine, and others have reported severe withdrawal cases, including withdrawal as the presentation of a stroke, as well as neonatal withdrawal (neonatal withdrawal has also been reported with paroxetine, fluoxetine, sertraline, and citalopram). In some venlafaxine withdrawal cases, successful discontinuation was eventually achieved by the addition of fluoxetine, which was later discontinued itself without difficulty.

Discontinuaton of Duloxetine
Eli Lilly The manufacturer of duloxetine - brand name Cymbalta - warns that "one should not suddenly stop taking this medicine, as this may cause withdrawal symptoms such as dizziness, pins and needles sensations, nausea, difficulty sleeping, intense dreams, headache, tremor, agitation or anxiety. Withdrawal symptoms are temporary and are not the same as addiction."

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

Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Tapering process may be moot for some patients, and they will still have discontinuation/withdrawal symptoms.

Many patients on the drug longer than the Lilly test trials on discontinuation (which only studied patients after 9 weeks of exposure to cymbalta), report anecdotal evidence of major withdrawals from cymbalta lasting from weeks to many months. Since duloxetine is a newer drug (FDA-approval 2004), not many peer-reviewed articles have been published on its adverse effects or withdrawal phenomena, and effect of long term use is still unknown.

Fluoxetine as intervention in SSRI Discontinuation Syndrome
Many doctors advise patients who are suffering from SSRI discontinuation syndrome to use fluoxetine as a substitute for their current drug. Substituting fluoxetine in the final stages of SSRI discontinuation, or post discontinuation, provides a rate of reduction of antidepressant which can minimize or eradicate withdrawal symptoms in the patient. Fluoxetine migrates slowly from the brain to the blood. The active metabolite of fluoxetine remains a long time in the brain because it is lipophilic, with a biological half life of 4 to 8 days (the longest of any SSRI). Therefore the level of the drug in the body falls slowly at a rate to which the brain can adjust when the dosage is reduced. Fluoxetine is also available in a liquid formula, allowing the physician to titrate the drug with greater ease.

In a randomized trial, abrupt interruption of antidepressant therapy for 5-8 days was associated with the emergence of new somatic and psychological symptoms with the highest degree in patients treated with paroxetine and to a lesser degree sertraline, with few symptoms seen with fluoxetine.


 * Intractable withdrawal from venlafaxine treated with fluoxetine was reported by WJ Giakas, JM Davis - Psychiatric Ann, 1997.
 * Fluoxetine for clomipramine withdrawal symptoms was reported by Benazzi F - Am J Psychiatry, 1999.


 * Fluoxetine was indicated to cover serotonergic discontinuation syndromes for cessation of paroxetine associated with withdrawal or discontinuation symptoms.

Neonatal withdrawal
The FDA issued a warning on July 19, 2006 to nursing mothers on SSRIs must discuss treatment with their physicians.

When taken by pregnant women, selective serotonin reuptake inhibitors (SSRIs) cross the placenta and have the potential to affect newborns. Although SSRIs have not been associated with congenital malformations, some evidence suggests that they are associated with neonatal complications such as neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension (PPH).

SSRI withdrawal syndromes been documented in neonates. Investigators found that by November 2003, a total of 93 cases of SSRI use associated with either neonatal convulsions or withdrawal syndrome had been reported. Subsequently, the authors of a study published in The Lancet concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with psychiatric disorders.

Controversy
Some critics of SSRIs claim that the widely-disseminated television and print advertising of SSRIs promotes an inaccurate message, oversimplifying what these medications actually do and deceiving the public.

Much of the criticism stems from questions about the validity of claims that SSRIs work by 'correcting' chemical imbalances. Without accurately measuring patients' neurotransmitter levels to allow for continuous monitoring during treatment, it is impossible to know if one is correctly targeting a deficient neurotransmitter (i.e. correcting an imbalance), reaching a desirable level, or even introducing too much of a particular neurotransmitter. Thus it has been argued that SSRIs can actually cause chemical imbalances and abnormal brain states. Hence it is purported that when a patient discontinues an SSRI, they may have a chemical imbalance due to the rapid cessation of the drug which is causing the discontinuation syndrome.

Most biopsychiatrists believe that, among other factors, the balance of neurotransmitters in the brain is a biological regulator of mental health. In this theory, emotions within a "normal" spectrum reflect a proper balance of neurochemicals, but abnormally extreme emotions, such as clinical depression, reflect an imbalance. Psychiatrists claim that medications regulate neurotransmitters and also claim they treat abnormal personalities by removing a neurochemical excess or replenishing a deficit (though the efficacy of antidepressants and antipsychotics is not undisputed ). On the other hand, Elliot Valenstein, a psychologist and neuroscientist, claims that the broad biochemical assertions and assumptions of mainstream psychiatry are not supported by evidence.

Critics suggest mainstream psychiatry theory is influenced by pharmaceutical companies' sales and marketing departments. Richard Smith (former editor of the British Medical Journal) wrote about how the drug industry can subtly influence what is published in the scholarly literature. He said, "I must confess that it took me almost a quarter of a century editing for the BMJ to wake up to what was happening."

One controversial critic of antidepressants, Peter Breggin, a physician who opposes the overuse of prescription medications to treat patients for mental health issues, predicted iatrogenic issues that SSRIs incur on a significant percentage of patients. Another prominent SSRI critic is David Healy.

In many cases SSRI drug manufacturers have withheld information from the FDA and the public to play down the risks and adverse effects associated with SSRIs, including information regarding withdrawals and discontinuation events. This had led to litigation with many of the pharmaceutical manufacturers of SSRIs.

In both the U.S. and United Kingdom (UK) class action lawsuits have been brought against GlaxoSmithKline (GSK) for withdrawal symptoms of paroxetine (Paxil in US, Seroxat in UK) not listed in the manufacturer's medication insert.