SSRI discontinuation syndrome (also known as
SSRI withdrawal or
cessation syndrome) is the
withdrawalWithdrawal 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/or alcohol...
that can occur during or following the interruption, lowering of dose, or discontinuation of regular SSRI or
SNRISNRI may refer to:* Serotonin-norepinephrine reuptake inhibitor* Strategic Naval Research Institute...
antidepressantAn antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia. Drugs including the monoamine oxidase inhibitors , tricyclic antidepressants , tetracyclic antidepressants , selective serotonin reuptake inhibitors , and serotonin-norepinephrine...
drug use. 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.
- 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.
History
The first report of
withdrawalWithdrawal 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/or alcohol...
symptoms occurring after SSRI discontinuation was for
fluvoxamineFluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor and is predominantly used to treat obsessive–compulsive disorder.-History:...
(brand names Luvox [US], Faverin [UK]) in 1992. The Committee on Safety of Medicines in the United Kingdom reported withdrawal symptoms involving
paroxetineParoxetine is a selective serotonin reuptake inhibitor 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
sertralineSertraline 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 CompanyEli 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 is a teaching hospital of Harvard Medical School and a biomedical research facility in 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 OrganizationThe World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public 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
paroxetineParoxetine is a selective serotonin reuptake inhibitor 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
fluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. Fluoxetine is approved for the treatment of major depression , obsessive-compulsive disorder , bulimia nervosa, anorexia nervosa, panic disorder and premenstrual dysphoric disorder...
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)."
List of SSRIs
Many drugs in this class are familiar in the USA through advertising, including the following:
(Trade names in parentheses)
- citalopram
Citalopram is an antidepressant drug used to treat major depression associated with mood disorders. It is also used on occasion in the treatment of body dysmorphic disorder and anxiety....
(Celexa, Cipramil, Celepram, Emocal, Sepram, Seropram)
- 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 is an antidepressant of the selective serotonin reuptake inhibitor class. Fluoxetine is approved for the treatment of major depression , obsessive-compulsive disorder , bulimia nervosa, anorexia nervosa, panic disorder and premenstrual dysphoric disorder...
(Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin [EUR])
- paroxetine
Paroxetine is a selective serotonin reuptake inhibitor antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
(Paxil, Seroxat, Aropax, Deroxat, Paroxat)
- 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)
- venlafaxine
Venlafaxine is an arylalkanolamine SNRI, although some authors dispute the claim that it inhibits NE reuptake. First introduced by Wyeth in 1993, it is licensed for the amelioration of MDD, as an anxiolytic, & comorbid indications. In 2007, venlafaxine was the sixth most commonly prescribed...
(Effexor)
- duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and it is as effective as venlafaxine in generalised anxiety disorder. It is a well tolerated and is considered a first line treatment strategy...
(Cymbalta)
- dapoxetine
Dapoxetine is a short-acting SSRI drug for the treatment of premature ejaculation in men. Dapoxetine is the only drug with regulatory approval for such treatment. Currently, it is approved for use in several European countries including Finland, Sweden, Portugal, Austria and Germany...
(Priligy)
- fluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor and is predominantly used to treat obsessive–compulsive disorder.-History:...
(Luvox, Faverin, Favoxil)
Venlafaxine and duloxetine are both members of the
SNRISerotonin-norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
class of antidepressant medication. SNRIs (serotonin-norepinephrine reuptake inhibitors) work on the
norepinephrineNoradrenaline or norepinephrine is a catecholamine with dual roles as a hormone and a neurotransmitter....
and
serotoninSerotonin is a monoamine neurotransmitter. It is found extensively in the gastrointestinal tract of animals, and about 80 to 90 percent of the human body's total serotonin is located in the enterochromaffin cells in the gut, where it is used to regulate intestinal movements...
neurotransmitters.
"Brain zaps" and sensations
Symptoms described as "brain zaps", "brain shocks," "brain shivers" or "head shocks" are a
withdrawalWithdrawal 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/or alcohol...
symptom experienced during discontinuation (or reduction of dose) of antidepressant drugs. The symptoms are widely variable in description and of unknown etiology; common descriptions include
dizzinessDizziness refers to an impairment in spatial perception and stability. It is considered imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or for a non-specific feeling such as giddiness or foolishness....
, electric shock-like sensations, sweating, nausea, insomnia, tremor, confusion, and
vertigoVertigo is a specific type of dizziness, a major symptom of a balance disorder. It is the sensation of spinning or swaying while the body is actually stationary with respect to the surroundings.The effects of vertigo may be slight...
. The
MedDRAMedDRA 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 reactionAn adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dose. The meaning of this expression differs from the meaning of "side effect", as this last expression might also imply that the effects can be beneficial...
reports (for use in
pharmacovigilancePharmacovigilance 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 SchemeThis article is about Human Medicines. For Veterinary Medicines, see the Suspected Adverse Reaction Surveillance Scheme.The Yellow Card Scheme is the UK system for collecting information on suspected Adverse Drug Reactions to medicines...
), is paraesthesia.
In a 1997 survey, 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
paroxetineParoxetine is a selective serotonin reuptake inhibitor 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.
Post SSRI sexual dysfunction
Post-SSRI sexual dysfunction (PSSD) is an
iatrogenicThe terms iatrogenesis and iatrogenic artifact refer to adverse effects or complications caused by or resulting from medical treatment or advice. In addition to harmful consequences of actions by physicians, iatrogenesis can also refer to actions by other healthcare professionals, such as...
type of
sexual dysfunctionSexual 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.-Categories:...
caused directly by the previous use of SSRIs. While apparently not uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs; however, these extreme lengths of time are fairly uncommon. It may represent a specific subtype of SSRI discontinuation syndrome.
One or more of the following
sexualHuman sexuality is how people experience the erotic and express themselves as sexual beings. Frequently driven by the desire for sexual pleasure, human sexuality has biological, physical and emotional aspects...
symptoms persist or begin after the discontinuation of SSRIs:
- Decreased or absent libido
Libido in its common usage means sexual desire; however, more technical definitions, such as those found in the work of Carl Jung, are more general, referring to libido as the free creative—or psychic—energy an individual has to put toward personal development or individuation.- History of the...
- Impotence or reduced vaginal lubrication
Vaginal lubrication is the naturally produced lubricating fluid that reduces friction during sexual intercourse. It is typically produced with women's sexual arousal, but also can be produced when there is no arousal...
- Difficulty initiating or maintaining an 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. Penile erection can also...
or becoming aroused
- Persistent sexual arousal syndrome
Persistent genital arousal disorder , also known as persistent sexual arousal syndrome , results in a spontaneous and persistent genital arousal, with or without orgasm or genital engorgement, unrelated to any feelings of sexual desire. It was first documented by Dr...
despite absence of desire
- Muted, delayed, or absent orgasm
An orgasm is the peak of the plateau phase of the sexual response cycle, characterized by an intense sensation of pleasure...
(anorgasmiaAnorgasmia is a form of sexual dysfunction sometimes classified as a psychiatric disorder in which the patient cannot achieve orgasm, even with adequate stimulation...
)
- Reduced or no experience of pleasure during orgasm
An orgasm is the peak of the plateau phase of the sexual response cycle, characterized by an intense sensation of pleasure...
(ejaculatory anhedoniaIn psychology, anhedonia is an inability to experience pleasure from normally pleasurable life events such as eating, exercise, and social or sexual interaction....
)
- Premature ejaculation
Premature ejaculation is a condition where 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 or clitoral sensitivity
- Genital anesthesia
Regional anaesthesia is anaesthesia affecting only a large part of the body, such as a limb. Regional anaesthetic techniques can be divided into central and peripheral techniques. The central techniques include so called neuroaxial blocks...
- Loss or decreased response to sexual
Human sexuality is how people experience the erotic and express themselves as sexual beings. Frequently driven by the desire for sexual pleasure, human sexuality has biological, physical and emotional aspects...
stimuli
- Reduced semen
Semen is an organic fluid, also known as seminal fluid, that usually contains spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...
volume
- Priapism
Priapism is a potentially harmful and painful medical condition in which the erect clitoris or penis does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours...
Lack of diagnostic criteria
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, ArizonaPhoenix is the capital and largest city of the U.S. state of Arizona, as well as the fifth most populous city in the United States...
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, and irritability."
A 2000 study at the Department of
PsychiatryPsychiatry is a medical specialty officially devoted to the treatment and study of mental disorders. The term was first coined by the German physician Johann Christian Reil in 1808....
at
Dalhousie UniversityDalhousie University is a university located in Halifax, Nova Scotia, Canada. As the largest post-secondary educational institution in the Maritime Provinces it offers a wide array of programs, including a medical program and the Dalhousie Law School. The chancellor is Mr. Fred Fountain; Dr...
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;
gaitGait is the pattern of movement of the limbs of terrestrial animals, including humans, during locomotion. 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 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
As described in the History section above, SSRI
withdrawalWithdrawal 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/or alcohol...
syndrome began to be called SSRI Discontinuation syndrome following a manufacturer-sponsored 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
addictionThe term "addiction" is used in many contexts to describe an obsession, compulsion, or excessive psychological dependence, such as: drug addiction The term "addiction" is used in many contexts to describe an obsession, compulsion, or excessive psychological dependence, such as: drug addiction The...
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 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 factorNerve growth factor , is a small secreted protein which induces the differentiation and survival of particular target neurons...
) in the absence of the SSRI, as well as
dopamineDopamine is a neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this phenethylamine functions as a neurotransmitter, activating the five types of dopamine receptors — D
1, D
2, D
3, D
4, and...
dependency, and an over-excited immune system.
The
central nervous systemThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
(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 cortexThe 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
autonomicAutonomic can refer to several things, including:*Autonomic nervous system*Autonomic Computing*Autonomic system *Autonomic Networking...
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
cognitionCognition is the scientific term for "the process of thought". Usage of the term varies in different disciplines; for example in psychology and cognitive science, it usually refers to an information processing view of an individual's psychological functions...
while the ventral is more related to emotional cognition.
A separate study demonstrated that changes in regional central blood volume of left
prefrontal cortexThe 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 nucleusThe 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 ScaleThe Hamilton Rating Scale for Depression , also known as the Hamilton Depression Rating Scale or HAM-D, is a 21-question 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 and...
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 imagingFunctional MRI or functional Magnetic Resonance Imaging is a type of specialized MRI scan. It measures the haemodynamic 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
dopamineDopamine is a neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this phenethylamine functions as a neurotransmitter, activating the five types of dopamine receptors — D
1, D
2, D
3, D
4, and...
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 doseCompliance is a medical term that means the degree to which a patient correctly follows medical advice. Most commonly, it refers to medication, or drug compliance, but may also mean use of medical appliances such as compression stockings, chronic wound care, self-directed physiotherapy exercises,...
may cause withdrawal symptoms. When discontinuing an SSRI with a short half-life, switching to a drug with a longer half-life (e.g.
fluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. Fluoxetine is approved for the treatment of major depression , obsessive-compulsive disorder , bulimia nervosa, anorexia nervosa, panic disorder and premenstrual dysphoric disorder...
or
citalopramCitalopram is an antidepressant drug used to treat major depression associated with mood disorders. It is also used on occasion in the treatment of body dysmorphic disorder and anxiety....
) and then discontinuing from that can decrease the likelihood and severity of withdrawal syndrome.
The condition may be avoided by either recommencing the original, and/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, 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.
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
Sexual dysfunction (loss of
libidoLibido in its common usage means sexual desire; however, more technical definitions, such as those found in the work of Carl Jung, are more general, referring to libido as the free creative—or psychic—energy an individual has to put toward personal development or individuation.- History of the...
, genital
anesthesiaAnesthesia, or anaesthesia , has traditionally meant the condition of having sensation blocked or temporarily taken away. This allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience...
,
erectile dysfunctionErectile dysfunction is a sexual dysfunction characterized by the inability to develop or maintain an erection of the penis sufficient for satisfactory sexual performance....
) that continued despite medication discontinuation years previously can occur in a very few cases.
Long term withdrawal syndromes outside of sexual dysfunction from SSRIs are not well documented. One Italian study found that in patients with
panic disorderPanic 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
agoraphobiaAgoraphobia is an anxiety disorder, often precipitated by the fear of having a panic attack in a setting from which there is no easy means of escape. As a result, sufferers of agoraphobia avoid public and/or unfamiliar places, especially large, open, spaces such as shopping malls or airports...
, 45% exhibited a discontinuation syndrome that disappeared within a month in all but 11%. Symptoms of the discontinuation syndrome include agitation, anxiety,
akathisiaAkathisia, 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 attackPanic attacks are very sudden, discrete periods of intense anxiety, mounting physiological arousal, fear, stomach problems and discomfort that are associated with a variety of somatic and cognitive symptoms. The onset of these episodes is typically abrupt, and may have no obvious triggers...
s, irritability, aggressiveness, worsening of mood,
dysphoriaDysphoria is an unpleasant or uncomfortable mood, such as sadness , anxiety, irritability, or restlessness. Etymologically, it is the opposite of euphoria....
, crying spells or mood lability, overactivity or hyperactivity,
depersonalizationDepersonalization is a malfunction or 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...
, decreased concentration, slowed thinking, confusion and memory/concentration difficulties.
Discontinuation of SNRIs
SNRISerotonin-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
serotoninSerotonin is a monoamine neurotransmitter. It is found extensively in the gastrointestinal tract of animals, and about 80 to 90 percent of the human body's total serotonin is located in the enterochromaffin cells in the gut, where it is used to regulate intestinal movements...
and
norepinephrineNoradrenaline or norepinephrine is a catecholamine with dual roles as a hormone and a neurotransmitter....
. The two mostly widely prescribed SNRIs are venlafaxine and duloxetine.
Venlafaxine
Sudden discontinuation of
venlafaxineVenlafaxine is an arylalkanolamine SNRI, although some authors dispute the claim that it inhibits NE reuptake. First introduced by Wyeth in 1993, it is licensed for the amelioration of MDD, as an anxiolytic, & comorbid indications. In 2007, venlafaxine was the sixth most commonly prescribed...
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,
dysphoriaDysphoria is an unpleasant or uncomfortable mood, such as sadness , anxiety, irritability, or restlessness. Etymologically, it is the opposite of euphoria....
, tremor, vertigo, irregularities in blood pressure, dizziness, visual and auditory hallucinations, feelings of abdominal distension, and
paresthesiaParesthesia is a sensation of tingling, 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,
cataplexyCataplexy is sudden and transient episode of loss of muscle tone, often triggered by emotions. It is a rare disease , but frequently affects people who have narcolepsy, a disorder whose principal signs are EDS , sleep attacks, sleep paralysis, hypnagogic hallucinations and disturbed night-time sleep...
, agitation, and worsening of depressive symptoms. Online help groups consistently mention withdrawal from Effexor 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 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.
Duloxetine
Eli LillyEli Lilly was the founder of Eli Lilly and Company.Eli Lilly may also refer to:* Eli Lilly and Company, a global pharmaceutical company...
, the manufacturer of
duloxetineDuloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and it is as effective as venlafaxine in generalised anxiety disorder. It is a well tolerated and is considered a first line treatment strategy...
- 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." However, addiction (specifically physical addiction) is defined by "the appearance of characteristic withdrawal symptoms when the substance is suddenly discontinued".
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 an intervention
Many doctors advise patients who are suffering from SSRI discontinuation syndrome to use
fluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. Fluoxetine is approved for the treatment of major depression , obsessive-compulsive disorder , bulimia nervosa, anorexia nervosa, panic disorder and premenstrual dysphoric disorder...
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
lipophilicLipophilicity, , 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 is a psychoactive/psychiatric drug used as an antidepressant and anxiolytic agent. It is a member of the tricyclic antidepressant chemical class...
withdrawal symptoms was reported in 1999 by F. Benazzi.
- Fluoxetine was indicated to cover 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 to nursing mothers on SSRIs must discuss treatment with their physicians.
When taken by pregnant women, selective serotonin reuptake inhibitors (SSRIs) cross the
placentaThe placenta is an organ unique to mammals that connects the developing fetus to the uterine wall. The placenta supplies the fetus with oxygen and food, and allows fetal waste to be disposed of via the maternal kidneys...
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 LancetLancet may refer to:* In medicine:** Lancet , a medical instrument with a double-edged blade** The Lancet, a medical journal** Lancet, a needle used in a blood-sampling device* In architecture:** Lancet arch** Lancet window* In fiction:...
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'
neurotransmitterNeurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...
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
neurotransmitterNeurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...
s in the
brainThe brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
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 depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and loss of interest or pleasure in normally enjoyable activities...
, 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 ).
Critics suggest mainstream psychiatry theory is influenced by pharmaceutical companies' sales and marketing departments.
Richard SmithRichard Smith is a British medical doctor, editor, and businessman.He is director of the Ovations initiative to combat chronic disease in the developing world...
(former editor of the
British Medical JournalBMJ is a partially open access medical journal. It is among the most influential and widely read peer-reviewed general academic journals in the field of medicine in the world....
) wrote about how the drug industry can subtly influence what is published in the scholarly
literatureAn academic journal is a peer-reviewed periodical in which scholarship relating to a particular academic discipline is published. Academic journals serve as forums for the introduction and presentation for scrutiny of new research, and the critique of existing research. Content typically takes the...
. 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 BregginPeter Roger Breggin is an American psychiatrist, and critic of biological psychiatry and psychiatric medication. In his books, he advocates replacing psychiatry's use of drugs and electroconvulsive therapy with humanistic and caring psychotherapy, education, and broader human services.Breggin is...
, 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 HealyDavid Healy is an Irish psychiatrist who is currently a professor in Psychological Medicine at Cardiff University School of Medicine, Wales. He is also the director of North Wales School of Psychological Medicine. He became the centre of controversy concerning the influence of the pharmaceutical...
.
In some cases SSRI manufacturers withheld information from the FDA and the public to play down the risks and adverse effects associated with SSRIs, including information regarding withdrawal syndrome (a.k.a. discontinuation effects). This led to litigation against some of the manufacturers. (See, e.g., Glaxosmithkline and paroxetine.)
In both the U.S. and United Kingdom (UK) class action lawsuits have been brought against
GlaxoSmithKline GlaxoSmithKline plc is a United Kingdom-based pharmaceutical, biological, and healthcare company. GSK is the world's second largest pharmaceutical company and a research-based company with a wide portfolio of pharmaceutical products covering anti-infectives, central nervous system, respiratory,...
(GSK) for withdrawal symptoms of paroxetine (brand name Paxil in the US, Seroxat in the UK) not listed in the manufacturer's medication insert; in the US, GSK had falsely advertised the drug on television as "not habit forming." (See the Controversy sections in the articles on Glaxosmithkline and paroxetine.)
See also
- Neuropsychopharmacology
Technical advancements in recent years have allowed progress toward the understanding of the brain and how drugs can be made to affect it. The term increasingly used to include all of the biological science involved is,...
- Neuropharmacology
Neuropharmacology is concerned with drug-induced changes in the functioning of cells in the nervous system..Within the discipline of neuropharmacology there are two branches, behavioral and molecular....
- Neurotoxicology
- 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 is the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and exogenous chemicals that alter normal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals...
- Psychoactive drug
A psychoactive drug, psychopharmaceutical or psychotropic substance is a chemical substance that acts primarily upon the central nervous system where it alters brain function, resulting in changes in perception, mood, consciousness and behavior...
External links