SSRI discontinuation syndrome
Encyclopedia
SSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a syndrome
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...

 that can occur following the interruption, dose reduction, or discontinuation of SSRI (selective serotonin re-uptake inhibitor) or SNRI antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...

 medications. The condition often begins between the time of reduction in dosage or complete discontinuation, depending on the elimination half-life of the drug and the patient's metabolism.

The particulars of the syndrome, in light of the multitude of prescribed agents, have been disputed. Nonetheless, double-blind placebo-controlled studies demonstrate statistically and clinically significant indications of difficulties with the discontinuing of SSRIs.

Signs and symptoms

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 which:
    • interfere with normal social, occupational, or other functioning.
    • are not due to another medical condition, drug use, or discontinuation.
    • are not due to a relapse of the condition for which the SSRI was originally prescribed.


Neurological

Symptoms described as "brain zaps", "brain shocks", "brain shivers", "head shocks", or "cranial zings" are a withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...

 symptom experienced during discontinuation (or reduction of dose) of antidepressant drugs. The symptoms are widely variable in description and are of unknown etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....

; common descriptions include dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....

, electric shock-like sensations,sweating
Sweating
Perspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...

, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...

, tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...

, confusion
ConFusion
ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...

, nightmares, and vertigo
Vertigo (medical)
Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...

. The MedDRA
MedDRA
MedDRA or Medical Dictionary for Regulatory Activities is a clinically validated international medical terminology used by regulatory authorities and the regulated biopharmaceutical industry throughout the entire regulatory process, from pre-marketing to post-marketing activities, and for data...

 "preferred term" for coding these types of symptoms in adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

 reports (for use in pharmacovigilance
Pharmacovigilance
Pharmacovigilance is the pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long term and short term side effects of medicines...

databases such as under the Yellow Card Scheme
Yellow Card Scheme
The Yellow Card Scheme is the UK system for collecting information on suspected Adverse Drug Reactions to medicines. The Scheme was founded in 1964 after the thalidomide disaster, and was developed by Dr Bill Inman....

) is paraesthesia.

In a 1997 survey in north-east England, a "sizable minority" of medical professionals were not confidently aware of the existence of antidepressant withdrawal symptoms. A 2005 review of adverse event reporting showed that descriptions of "electric shocks" from patients on paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...

 had been reported more frequently than some other symptoms.

History

The first report of withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...

 symptoms occurring after SSRI discontinuation was for fluvoxamine
Fluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...

 (brand names Luvox (US), Faverin (UK)) in 1992. The Committee on Safety of Medicines in the United Kingdom reported withdrawal symptoms involving paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...

 (Paxil, Seroxat) in 1993, and the American Journal of Psychiatry revealed the same for sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...

 (Zoloft, Lustral) the following year.

In 1996, Eli Lilly and Company
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...

 sponsored a symposium to address the increasing number of reports of patients who had difficult symptoms after going off their antidepressants:
By then it had become clear that drug-company estimates that at most a few percent of those who took antidepressants would have a hard time getting off were far too low. Jerrold Rosenbaum and Maurizio Fava, researchers at Massachusetts General Hospital
Massachusetts General Hospital
Massachusetts General Hospital is a teaching hospital and biomedical research facility in the West End neighborhood of Boston, Massachusetts...

, found that among people getting off antidepressants, anywhere from 20 percent to 80 percent (depending on the drug) suffered what was being called antidepressant withdrawal (but which, after the symposium, was renamed “discontinuation syndrome”).


The World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 (WHO) continues to track withdrawal syndrome, and notes:
SSRIs are an example of how a conceptual confusion over terminology can affect proper reporting, interpretation and communication of adverse drug reactions related to dependence. To avoid the association with dependence, an increasing number of researchers have used a different term, discontinuation syndrome, instead of withdrawal syndrome. The number of hits for discontinuation syndrome in searches of the international medical literature began to increase, relative to the occurrence of withdrawal syndrome, in 1997 after [the Eli Lilly] symposium on antidepressant discontinuation syndrome held in 1996. In fact, dependence syndrome has been reported to the Uppsala Monitoring Centre for all SSRIs through the same postmarketing surveillance systems, although there are significantly fewer reports of dependence syndrome than of withdrawal syndrome.


The same WHO note ranks antidepressants according to withdrawal, with paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...

 having the highest number of withdrawal syndrome reports and fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...

 the highest number of drug dependence reports; the note concludes, "Three SSRIs are among the 30 highest-ranking drugs in the list of drugs for which drug dependence has ever been reported to the Uppsala Monitoring Centre database; a total of 269 reports had been received as of June 2002 (109 reports for fluoxetine, 91 for paroxetine and 69 for sertraline)."

Cause

The cause is the abrupt cessation of one of the SSRIs or SNRIs.
  • citalopram
    Citalopram
    Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...

     (Celexa, Cipramil, Celepram, Emocal, Sepram, Seropram)
  • escitalopram
    Escitalopram
    Escitalopram is an antidepressant of the selective serotonin reuptake inhibitor class. It is approved by the U.S...

     (Lexapro, Cipralex, Esertia, Esipram)
  • fluoxetine
    Fluoxetine
    Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...

     (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin [EUR])
  • paroxetine
    Paroxetine
    Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...

     (Paxil, Seroxat, Pexeva, Aropax, Deroxat, Paroxat)
  • sertraline
    Sertraline
    Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...

     (Zoloft, Lustral, Serlain)
  • dapoxetine
    Dapoxetine
    Dapoxetine is a short-acting selective serotonin reuptake inhibitor marketed for the treatment of premature ejaculation in men. Dapoxetine is the only drug with regulatory approval for such an indication. Currently, it is approved in several European countries, including Finland, Sweden,...

     (Priligy)
  • fluvoxamine
    Fluvoxamine
    Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...

     (Luvox, Faverin, Favoxil)
  • venlafaxine hydrochloride (Effexor XR)
  • duloxetine
    Duloxetine
    Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...

     (Cymbalta)
  • desvenlafaxine
    Desvenlafaxine
    Desvenlafaxine , also known as O-desmethylvenlafaxine, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class developed and marketed by Wyeth . Desvenlafaxine is a synthetic form of the major active metabolite of venlafaxine...

     (Pristiq)
  • tramadol
    Tramadol
    Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...

     (Ultram)

Post-SSRI sexual dysfunction

According to one source, post-SSRI sexual dysfunction (PSSD) is an iatrogenic type of sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....

 caused directly by the previous use of SSRI antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...

s.

While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs. This condition has not been well-established or proven in the field of medicine, thus patients are not warned of the potential condition by their physicians and it is not listed in consumer information leaflets.

One or more of the following sexual
Human sexuality
Human sexuality is the awareness of gender differences, and the capacity to have erotic experiences and responses. Human sexuality can also be described as the way someone is sexually attracted to another person whether it is to opposite sexes , to the same sex , to either sexes , or not being...

 symptoms may persist or begin after the discontinuation of SSRIs:
  • Decreased or absent libido
    Libido
    Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...

  • Impotence or reduced vaginal lubrication
    Vaginal lubrication
    Vaginal lubrication is a lubricating fluid that is naturally produced in a woman's vagina. Vaginal lubrication or moistness is present at all times, but production increases significantly during a woman's sexual arousal in anticipation of sexual intercourse...

  • Difficulty initiating or maintaining an erection
    Erection
    Penile erection is a physiological phenomenon where the penis becomes enlarged and firm. Penile erection is the result of a complex interaction of psychological, neural, vascular and endocrine factors, and is usually, though not exclusively, associated with sexual arousal...

     or becoming aroused
  • Persistent genital arousal disorder despite absence of desire
  • Muted, delayed, or absent orgasm
    Orgasm
    Orgasm is the peak of the plateau phase of the sexual response cycle, characterized by an intense sensation of pleasure...

     (anorgasmia
    Anorgasmia
    Anorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...

    )
  • Reduced or no experience of pleasure during orgasm
    Orgasm
    Orgasm is the peak of the plateau phase of the sexual response cycle, characterized by an intense sensation of pleasure...

     (ejaculatory anhedonia
    Anhedonia
    In psychology and psychiatry, anhedonia is defined as the inability to experience pleasure from activities usually found enjoyable, e.g. hobbies, exercise, social interaction or sexual activity....

    )
  • Premature ejaculation
    Premature ejaculation
    Premature ejaculation is a condition in which a man ejaculates earlier than he or his partner would like him to. Premature ejaculation is also known as rapid ejaculation, rapid climax, premature climax, or early ejaculation....

  • Weakened penile, vagina
    Vagina
    The vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in female placental mammals and marsupials, or to the cloaca in female birds, monotremes, and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the...

    l, or clitoral sensitivity
  • Genital anesthesia
    Anesthesia
    Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...

  • Loss or decreased response to sexual
    Human sexuality
    Human sexuality is the awareness of gender differences, and the capacity to have erotic experiences and responses. Human sexuality can also be described as the way someone is sexually attracted to another person whether it is to opposite sexes , to the same sex , to either sexes , or not being...

     stimuli
  • Reduced semen
    Semen
    Semen is an organic fluid, also known as seminal fluid, that may contain spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...

     volume
  • Priapism
    Priapism
    Priapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...

     (persistent erectile state of the penis or clitoris)

Diagnosis

Although most 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 very distressing and intensely 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.

With the lack of a definition based on consensus criteria for the syndrome, a discontinuation panel met in Phoenix, Arizona
Phoenix, Arizona
Phoenix is the capital, and largest city, of the U.S. state of Arizona, as well as the sixth most populated city in the United States. Phoenix is home to 1,445,632 people according to the official 2010 U.S. Census Bureau data...

 in 1997 and stated:
"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, irritability and aggressiveness."


A 2000 study at the Department of Psychiatry
Psychiatry
Psychiatry is the medical specialty devoted to the study and treatment of mental disorders. These mental disorders include various affective, behavioural, cognitive and perceptual abnormalities...

 at Dalhousie University
Dalhousie University
Dalhousie University is a public research university located in Halifax, Nova Scotia, Canada. The university comprises eleven faculties including Schulich School of Law and Dalhousie University Faculty of Medicine. It also includes the faculties of architecture, planning and engineering located at...

 in Halifax, Nova Scotia constructed diagnostic 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
Paresthesia
Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...

; anxiety; diarrhea; fatigue; gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...

 instability; headache; insomnia; irritability; nausea or emesis; tremor; and visual disturbances.

Due to the 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

As described in the History section above, SSRI withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...

 syndrome began to be called SSRI Discontinuation syndrome following a symposium in 1996; since then, the terms have been used interchangeably. 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 discontinuing their use can produce both somatic and psychological symptoms.

Critics argue that the pharmaceutical industry has a vested interest in creating a distinction between addiction
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...

 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

The exact mechanism of SSRI discontinuation syndrome is unknown, and may be due to 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
Nerve growth factor
Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...

) in the absence of the SSRI, as well as dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 dependency, and an over-excited immune system.

The central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 (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 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
Anterior cingulate cortex
The anterior cingulate cortex is the frontal part of the cingulate cortex, that resembles a "collar" form around the corpus callosum, the fibrous bundle that relays neural signals between the right and left cerebral hemispheres of the brain...

 (ACC) function. The ACC appears to play a role in a wide variety of autonomic
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...

 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
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...

 while the ventral is more related to emotional cognition.

A separate study demonstrated that changes in regional central blood volume of left prefrontal cortex
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...

 and left caudate nucleus
Caudate nucleus
The caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...

 correlate with the emergence of discontinuation symptoms and increased Hamilton Depression Rating Scale
Hamilton Depression Rating Scale
The Hamilton Rating Scale for Depression , also known as the Hamilton Depression Rating Scale or abbreviated to HAM-D, is a multiple choice questionnaire that clinicians may use to rate the severity of a patient's major depression. Max Hamilton originally published the scale in 1960 and reviewed...

 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 maps were obtained via dynamic susceptibility functional magnetic resonance imaging
Functional magnetic resonance imaging
Functional magnetic resonance imaging or functional MRI is a type of specialized MRI scan used to measure the hemodynamic response related to neural activity in the brain or spinal cord of humans or other animals. It is one of the most recently developed forms of neuroimaging...

 (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 dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

rgic 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
Compliance (medicine)
In medicine, compliance describes the degree to which a patient correctly follows medical advice...

 may cause withdrawal symptoms. When discontinuing an SSRI with a short half-life, switching to a drug with a longer half-life (e.g. fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...

 or citalopram
Citalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...

) and then discontinuing from that can decrease the likelihood and severity of withdrawal syndrome.

The condition may be avoided by either recommencing the original or lesser dose of the SSRI (or a similar SSRI), or slowly reducing 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. Gradual discontinuation, or tapering, or titration, can be accomplished by breaking pills into parts or using a graduated oral syringe with the liquid form. Alternatively, a compounding pharmacy may take one's prescription and divide it into smaller graduated doses. For example, a 20 mg prescription of Cymbalta, which comes in gel capsules containing tiny sphere-shaped pellets, may be divided into 20, 15, 10, 5, and 2.5 mg doses.

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. Benzodiazepines may be used for insomnia, although it's very important to note that benzodiazepine withdrawal is known to be severe and long-lived. If symptoms of SSRI discontinuation are severe, or do not respond to symptom management, the antidepressant can be reinstated and then withdrawn more cautiously.

People experiencing severe withdrawal symptoms may taper dosage by 5% per week (or month, or even longer) in order to avoid a drastic drop in serotonergic activity; however, even gradual reductions can produce withdrawal symptoms in some cases. Switching to an SSRI with a longer half-life, then tapering off that, may eliminate withdrawal symptoms; see "Fluoxetine as intervention in SSRI Discontinuation Syndrome" below.

Persistent adverse effects

In a very few cases, discontinuation of SSRIs may result in sexual dysfunction (loss of libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...

, genital anesthesia
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...

, erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....

) that persists for years after the fact.

Long term withdrawal syndromes outside of sexual dysfunction from SSRIs are not well documented. One Italian study found that in patients with panic disorder
Panic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...

 and agoraphobia
Agoraphobia
Agoraphobia is an anxiety disorder defined as a morbid fear of having a panic attack or panic-like symptoms in a situation from which it is perceived to be difficult to escape. These situations can include, but are not limited to, wide-open spaces, crowds, or uncontrolled social conditions...

, 45% exhibited a discontinuation syndrome that disappeared within a month in all but 11%. Symptoms of the discontinuation syndrome include agitation, anxiety, akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...

, panic attack
Panic attack
Panic attacks are periods of intense fear or apprehension that are of sudden onset and of relatively brief duration. Panic attacks usually begin abruptly, reach a peak within 10 minutes, and subside over the next several hours...

s, irritability, hostility, aggressiveness, worsening of mood, dysphoria
Dysphoria
Dysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...

, crying spells or mood lability, overactivity or hyperactivity, depersonalization
Depersonalization
Depersonalization is an anomaly of the mechanism by which an individual has self-awareness. It is a feeling of watching oneself act, while having no control over a situation. Sufferers feel they have changed, and the world has become less real, vague, dreamlike, or lacking in significance...

, decreased concentration, slowed thinking, confusion, and memory/concentration difficulties.

Discontinuation of SNRIs

SNRI
Serotonin-norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...

s affect both reuptake inhibition of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

 and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

. The two mostly widely prescribed SNRIs are venlafaxine and duloxetine. To these has been added desvenlafaxine. In addition, the widely used analgesic Tramadol
Tramadol
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...

, which is molecularly similar to venlafaxine, has been cited as it has SNRI properties which typically are known to affect patients after 3 months or more use in theraputic doses of 400 mg per day.

Venlafaxine

Sudden discontinuation of venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...

 (brand name Effexor) 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 reflects 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 a short half-life such as paroxetine.

Symptoms of discontinuation are similar to other antidepressants including irritability, restlessness, headache, nausea, fatigue, excessive sweating, dysphoria
Dysphoria
Dysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...

, tremor, vertigo, irregularities in blood pressure, dizziness, visual and auditory hallucinations, feelings of abdominal distension, and paresthesia
Paresthesia
Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...

. Other non-specific mental symptoms may include impaired concentration, bizarre dreams, delirium, cataplexy
Cataplexy
Cataplexy is a sudden and transient episode of loss of muscle tone, often triggered by emotions. It is a rare disease , but affects roughly 70% of people who have narcolepsy...

, agitation, hostility, and worsening of depressive symptoms. Online help groups consistently mention withdrawal from venlafaxine as triggering dreams of a particularly distressing and hellish quality.

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 neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

al 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. Additionally, use of tramadol has been proven effective as anti-depressant withdrawal aid especially with venlafaxine.

Duloxetine

Eli Lilly and Company
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...

, the manufacturer of duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...

 (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." These responses could constitute physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...

 on the drug, but SSRI users do not experience the craving, impulsive use, or long-term relapse risk seen in drug addiction
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...

.

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, aggressiveness, 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.

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 effects of long term use is still unknown.

Fluoxetine as an intervention

Many doctors advise patients who are suffering from SSRI discontinuation syndrome to use fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...

 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
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...

, 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 (e.g., with an oral syringe).

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.
  • Fluoxetine for clomipramine
    Clomipramine
    Clomipramine is a tricyclic antidepressant . It was developed in the 1960s by the Swiss drug manufacturer Geigy and has been in clinical use worldwide ever since.- Indications :...

     withdrawal symptoms was reported in 1999 by F. Benazzi.

  • Fluoxetine was indicated to cover serotonergic
    Serotonergic
    Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...

     discontinuation syndromes for cessation of paroxetine associated with withdrawal or discontinuation symptoms.

Neonatal withdrawal

The U.S. Food and Drug Administration (FDA) issued a warning on July 19, 2006 that nursing mothers on SSRIs must discuss treatment with their physicians.

When taken by pregnant women, selective serotonin reuptake inhibitors (SSRIs) cross the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...

 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 have 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
The Lancet
The Lancet is a weekly peer-reviewed general medical journal. It is one of the world's best known, oldest, and most respected general medical journals...

 concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with psychiatric disorders.

See also

  • Black box warning
    Black box warning
    In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...

  • Neuropsychopharmacology
    Neuropsychopharmacology
    Neuropsychopharmacology is an interdisciplinary science related to psychopharmacology and fundamental neuroscience...

  • Neuropharmacology
    Neuropharmacology
    Neuropharmacology is the study of how drugs affect cellular function in the nervous system. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior , including the study of how drug dependence...

  • Neurotoxicology
  • Neuropsychotoxicology
    Neuropsychotoxicology
    Neuropsychotoxicology is the subdiscipline of neurotoxicology concerned with the study of toxins or toxicants that have adverse effects on the brain, specifically, those affecting behavior and neurological function....

  • Pharmacology
    Pharmacology
    Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...

  • Psychoactive drug
    Psychoactive drug
    A psychoactive drug, psychopharmaceutical, or psychotropic is a chemical substance that crosses the blood–brain barrier and acts primarily upon the central nervous system where it affects brain function, resulting in changes in perception, mood, consciousness, cognition, and behavior...


External links

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
x
OK