SSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a condition that can occur during or following the interruption, lowering of dose or discontinuation of regular SSRI or SNRI antidepressant drug usage. The condition often begins between 24 hours to one week after reduction in dosage or complete discontinuation, depending on the elimination half-life of the drug. The prescribing labels of SSRIs acknowledge the possibility of "intolerable" discontinuation reactions, and some patients have extreme difficulty discontinuing use from SSRI drugs. SSRI is an acronym that stands for several things: It is a class of antidepressants called selective serotonin reuptake inhibitor SSRI also is used as the stock symbol for Silver Standard Resources Inc. ... Serotonin norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant used in the treatment of clinical depression and other affective disorders. ... A recent form of antidepressant medication - Prozac Serotonin-norepinephrine reuptake inhibitor, Venlafaxine An antidepressant, in the most common usage, is a medication taken to alleviate clinical depression or dysthymia (milder depression). ... For other meanings, see Drug (disambiguation). ... The elimination half-life of a drug (or any xenobiotic agent) refers to the timecourse necessary for the quantity of the xenobiotic agent in the body (or plasma concentration) to be reduced to half of its original level through various elimination processes. ...

The indicators of SSRI discontinuation syndrome are the following:

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

History

The first report of withdrawal symptoms occurring after SSRI discontinuation was in 1992 with fluvoxamine.^[1] In 1993 the Committee of Safety of Medicines in the United Kingdom reported withdrawal symptoms with paroxetine.^[2] Sertraline withdrawal reports appeared in 1994.^[3] Withdrawal, also known as withdrawal syndrome, refers to the characteristic signs and symptoms that appear when a drug that causes physical dependence is regularly used for a long time and then suddenly discontinued or decreased in dosage. ...

List of SSRIs

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

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

Venlafaxine and duloxetine are both members of the SNRI class of antidepressant medication. SNRIs (serotonin-norepinephrine reuptake inhibitors) work on the norepinephrine and serotonin neurotransmitters. Citalopram is an antidepressant drug used to treat depression associated with mood disorders. ... This article or section does not cite its references or sources. ... Fluoxetine hydrochloride (Prozac) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. ... Paroxetine or paroxetine hydrochloride is a selective serotonin reuptake inhibitor (SSRI) antidepressant. ... “Lustral” redirects here. ... Venlafaxine hydrochloride is a prescription antidepressant first introduced by Wyeth in 1993. ... Duloxetine hydrochloride (brand names: Cymbalta/Yentreve and in parts of Europe known as Xeristar or Ariclaim) is a drug that primarily targets major depressive disorders (MDD), pain related to diabetic peripheral neuropathy and in some countries stress urinary incontinence (SUI). ... Dapoxetine is the International Nonproprietary Name of a drug currently being considered for approval by the FDA for the treatment of premature ejaculation in men, which would make it the first drug approved for such treatment. ... Fluvoxamine (brand name as Luvox®, Faverin®, Fevarin® and Dumyrox®) is an antidepressant which functions pharmacologically as a selective serotonin reuptake inhibitor. ... Serotonin norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant used in the treatment of clinical depression and other affective disorders. ...

Note that trazodone is not a typical member of the SSRIs - while it is a serotonin reuptake inhibitor, it is believed that its anti-depressant properties may be due to some of its other pharmacodynamic properties rather than its effect on serotonin reuptake. That said, it does still share many properties of the typical SSRIs, especially the possibility of the 'discontinuation syndrome'. Trazodone (trade names Desyrel, Molipaxin, Trittico, Thombran, Trialodine) is a psychoactive compound with sedative, anxiolytic, and antidepressant properties. ...

Symptoms

Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated SSRIs. Just because a side effect is stated here, it does not mean that all people using one of these medicines will experience that or any side effect. The discontinuation (specifically when abrupt) of antidepressants can result in a syndrome of adverse events, including somatic, mood and psychomotor reactions.

• Dry mouth
• Headache
• Insomnia
• Somnolence
• Dizziness, or Orthostatic hypotension^[4]
• Fatigue
• Cataplexy
• Increased sweating
• Decreased appetite and weight loss
• Intraocular pressure or blurred vision
• Paresthesia
• Disturbances of the gut, such as nausea, constipation, diarrhea, indigestion, vomiting
• Tremor
• Nightmares
• Akathisia, (anxiety, nervousness, agitation, suicidal thoughts) ^[5]
• Palpitations
• Decreased sex drive or difficulty achieving orgasm
• Impotence or delayed ejaculation
• Hot flashes
• Taste disturbances
• Dysphoria
• Difficulty passing urine
• Increase in blood pressure or heart rate
• Cold hands or feet
• Jaundice
• Inflammation of the liver
• Depersonalization
• Myoclonus (involuntary muscle twitching)
• Tinnitus
• Extreme yawning, feeling of lack of Oxygen
• Extreme sensitivity to fluorescent light

Xerostomia is the medical term for a dry mouth due to a lack of saliva. ... A headache (cephalalgia in medical terminology) is a condition of pain in the head; sometimes neck or upper back pain may also be interpreted as a headache. ... This article or section does not cite any references or sources. ... Somnolence (or drowsiness) is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods. ... // Pre-syncope is a sensation of feeling faint. ... Orthostatic hypotension (also known as postural hypotension and, colloquially, as head rush or a dizzy spell) is a sudden fall in blood pressure, typically greater than 20/10 mm Hg, that occurs when a person assumes a standing position. ... The word fatigue is used in everyday living to describe a range of afflictions, varying from a general state of lethargy to a specific work induced burning sensation within muscle. ... Cataplexy is a medical condition which often affects people who have narcolepsy, a disorder whose principal signs are EDS (Excessive Daytime Sleepiness), sleep attacks, and disturbed nighttime sleep. ... Paresthesia or paraesthesia (in British English) is a sensation of tingling, pricking, or numbness of a persons skin with no apparent long-term physical effect, more generally known as the feeling of pins and needles or of a limb being asleep. // Transient paresthesia is the temporary sensation of tingling... For the film see Tremors (film). ... In common current usage, the term nightmare refers to dreams of particular intensity, with content that the sleeper finds disturbing, related either to physiological causes, such as a high fever, or to psychological ones, such as unusual trauma or stress in the sleepers life. ... Akathisia (or acathisia) is an often extremely unpleasant subjective sensation of inner restlessness that manifests itself with an inability to sit still or remain motionless, hence the origin of its name: Greek a (without) + kathesis (sitting). ... This article includes a list of works cited or a list of external links, but its sources remain unclear because it lacks in-text citations. ... Anxiety is a complex combination of the feeling of fear, apprehension and worry often accompanied by physical sensations such as palpitations, chest pain and/or shortness of breath. ... Agitation may have the following special meanings Agitation, an emotional state Agitation, putting into motion (by shaking or stirring) Agitation, a term from the lexicon of Communists: political activities aimed at urging people to do something This is a disambiguation page — a navigational aid which lists other pages that... Suicide (from Latin sui caedere, to kill oneself) is the act of willfully ending ones own life. ... A palpitation is an abnormal, rapid beating of the heart, brought on by overexertion, disease or drugs. ... Impotence or, more clinically, erectile dysfunction is the inability to develop or maintain an erection of the penis for satisfactory sexual intercourse regardless of the capability of ejaculation. ... A Hot flush (sometimes hot flash or night sweat) is a symptom of Menopause and changing hormone levels which typically expresses itself at night as periods of intense heat with sweating and rapid heartbeat and may typically last from two to thirty minutes on each occasion. ... Look up dysphoria in Wiktionary, the free dictionary. ... Jaundice, also known as icterus (attributive adjective: icteric), is a yellowing of the skin, conjunctiva (a clear covering over the sclera, or whites of the eyes) and mucous membranes caused by increased levels of bilirubin in red blooded animals. ... This article or section includes a list of works cited but its sources remain unclear because it lacks in-text citations. ... Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. ... Tinnitus (IPA pronunciation: or ,[1] from the Latin word for ringing[2]) is the perception of sound in the human ear in the absence of corresponding external sound(s). ...

"Electric shock" sensations

"Brain zaps", also known as "the electric brain thing", "brain shivers," "brain shocks," "battery head", "blips," or "brain spasms" are a fairly common and notorious withdrawal symptom experienced during discontinuation (or reduction of dose) of SSRI and SNRI antidepressant drugs. Brain zaps, (proposed name: myalotinasis from Greek for brain + jolt) also known as the electric brain thing, brain shivers, brain shocks, battery head, blips, or brain spasms, are a fairly common and notorious withdrawal symptom experienced during discontinuation (or reduction of dose) of SSRI and SNRI antidepressant drugs. ... SSRI is an acronym that stands for several things: It is a class of antidepressants called selective serotonin reuptake inhibitor SSRI also is used as the stock symbol for Silver Standard Resources Inc. ... Serotonin norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant used in the treatment of clinical depression and other affective disorders. ... A recent form of antidepressant medication - Prozac Serotonin-norepinephrine reuptake inhibitor, Venlafaxine An antidepressant, in the most common usage, is a medication taken to alleviate clinical depression or dysthymia (milder depression). ...

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

The electric shock sensations reported with neck flexion seem identical to Lhermitte's sign, which appears with dysfunction of the posterior spinal cord. This suggests change at a neuronal level.^[6] In anatomy, Flexion is movement whereby bones or other objects are brought closer together. ... Lhermittes Sign is a sign used to help diagnose Multiple Sclerosis and is indicated by electric-like sensations caused by flexing ones neck. ... The Spinal cord nested in the vertebral column. ...

Post SSRI Sexual Dysfunction

Post SSRI Sexual Dysfunction (PSSD)^[7] is an iatrogenic type of sexual dysfunction caused directly by the previous use of SSRIs. While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs. It may represent a specific subtype of SSRI discontinuation syndrome. Post SSRI Sexual Dysfunction (PSSD) is a type of sexual dysfunction caused by the previous use of SSRI antidepressants. ... An iatrogenic (pronounced , IPA) condition is a state of ill health or adverse effect caused by medical treatment, usually due to mistakes made in treatment. ... Sexual dysfunction or sexual malfunction (see also sexual function) is difficulty during any stage of the sexual act (which includes desire, arousal, orgasm, and resolution) that prevents the individual or couple from enjoying sexual activity. ...

One or more of the following sexual symptoms persist or begin after the discontinuation of SSRIs: Human sexuality is the expression of sexual feelings. ...

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

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. ... Impotence or, more clinically, erectile dysfunction is the inability to develop or maintain an erection of the penis for satisfactory sexual intercourse regardless of the capability of ejaculation. ... Vaginal lubrication is the naturally produced lubricating fluid that reduces friction during sexual intercourse. ... The erection of the penis, clitoris or a nipple is its enlarged and firm state. ... Sexual arousal is the process and state of an animal being ready for sexual intercourse. ... 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. ... Orgasm is the conclusion of the plateau phase of the sexual response cycle, and is experienced by both males and females. ... Anorgasmia (also known as Retarded Ejaculation in males) is a form of sexual dysfunction, sometimes classified as a psychiatric disorder, where the patient cannot achieve orgasm, even with adequate stimulation. ... Orgasm is the conclusion of the plateau phase of the sexual response cycle, and is experienced by both males and females. ... In psychology, anhedonia is a patients inability to experience pleasure from normally pleasurable life events such as eating, exercise, and social/sexual interactions. ... It has been suggested that Drugs specifically targeted to treat premature ejaculation be merged into this article or section. ... The penis (plural penises or penes) or phallus is an external male sexual organ. ... A womans clitoris extends from the visible portion to a point below the pubic bone. ... It has been suggested that this article or section be merged with Nerve block. ... Human sexuality is the expression of sexual feelings. ... Horse semen being collected for breeding purposes. ... Fresco of Priapus, House of the Vettii, Pompeii. ...

Lack of Diagnostic Critiera

Although SSRIs are widely used and generally considered safe, an abrupt cessation, or rapid tapering of SSRI use may result in a discontinuation syndrome that can mimic serious illness and can be distressing and uncomfortable. Several pharmacokinetic and pharmacodynamic factors influence the frequency and onset of these symptoms. When allowed to run its course, the syndrome duration is variable (usually one to several weeks) and ranges from mild-moderate intensity in most patients, to extremely distressing in a smaller number of patients who may have side effects for months, and in extremely rare cases permanently. Pharmacokinetics is a branch of pharmacology dedicated to the study of the time course of substances and their relationship with an organism or system. ... Pharmacodynamics is the study of the biochemical and physiological effects of drugs and the mechanisms of drug action and the relationship between drug concentration and effect. ...

With the lack of a definition based on consensus criteria for the syndrome, a discontinuation panel met in Phoenix, Arizona in 1997 and purported that: Nickname: Location in Maricopa County and the state of Arizona Coordinates: Country United States State Arizona Counties Maricopa Incorporated February 25, 1881 Government  - Type Council-Manager  - Mayor Phil Gordon (D) Area  - City  515. ...

"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."^[8]

A 2000 study at the Department of Psychiatry at Dalhousie University in Halifax, Nova Scotia constructed a diagonistic criteria for SSRI discontinuation syndrome. These criteria are 2 or more of the following symptoms developing within 1 to 7 days of discontinuation or reduction in dosage of an SSRI after at least 1 month's use, when these symptoms cause clinically significant distress or impairment and are not due to a general medical condition or recurrence of a mental disorder: dizziness, light-headedness, vertigo or feeling faint; shock-like sensations or paresthesia; anxiety; diarrhea; fatigue; gait instability; headache; insomnia; irritability; nausea or emesis; tremor; and visual disturbances.^[9] Psychiatrist redirects here. ... Dalhousie University is a university located on the Halifax Peninsula in the Halifax Regional Municipality, Nova Scotia, Canada. ... Motto: Template:Unhide = E Mari Merces (Wealth from the Sea) Logo: Location City Information Established: April 1, 1996 Area: (former city) 79. ... A gait can refer to: a particular way or manner of moving on foot: walking and running are the two basic human gaits; see also gait analysis and Gait (human). ... Vomiting (or emesis) is the forceful expulsion of the contents of ones stomach through the mouth. ...

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. In medicine, a clinical trial (synonyms: clinical studies, research protocols, medical research) is a research study. ...

Definition of Withdrawal

The term withdrawal has been used in the past for SSRI discontinuation syndrome; however, discontinuation symptoms and classical drug withdrawal are different. Thus, the use of proper terminology when discussing this phenomenon is still ambiguous. SSRIs are not addictive in the conventional medical use of the word (i.e. animals given free access to the drug do not actively seek it out and do not seek to increase the dose), but suddenly discontinuing their use is known to produce both somatic and psychological symptoms, as described by researchers.^[10] Withdrawal, also known as withdrawal syndrome, refers to the characteristic signs and symptoms that appear when a drug that causes physical dependence is regularly used for a long time and then suddenly discontinued or decreased in dosage. ...

Critics argue that the pharmaceutical industry has a vested interest in creating a distinction between addiction to recreational or illegal drugs and dependence on antidepressants. Arguments against the use of the term 'withdrawal' are primarily predicated on not frightening patients or alienating potential customers who may or may not need the medication. ^[11] 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. Pharmacology (in Greek: pharmacon is drug, and logos is science) is the study of how chemical substances interfere with living systems. ... Addiction is a chronic or recurrent condition proposed to be precipitated by one or more of the following: genetic, biological/pharmacological and social factors. ...

Mechanism

Further information: Chemical synapse

Antidepressant withdrawal effects do not indicate addiction in the strict medical sense, but are rather the results of the brain attempting to reach neurochemical stability after an abrupt change. The exact mechanism of SSRI discontinuation syndrome is unknown, and may be a variety of factors. Continuing research on discontinuation/withdrawal syndrome has attributed SSRI discontinuation syndrome to electrophysiological changes in the brain (particularly on the 5-HT receptor), and electropysiological changes in the body (nerve growth factor) in the absence of the SSRI, as well as dopamine dependency, and an over-excited immune system. Illustration of the major elements in a prototypical synapse. ... Addiction is a chronic or recurrent condition proposed to be precipitated by one or more of the following: genetic, biological/pharmacological and social factors. ... A sketch of the human brain by artist Priyan Weerappuli, imposed upon the profile of Michelangelos David. ... Neurochemistry is a branch of neuroscience that is heavily devoted to the study of neurochemicals. ... Serotonin (5_hydroxytryptamine, or 5_HT) is a monoamine neurotransmitter synthesised in serotonergic neurons in the central nervous system and enterochromaffin cells in the gastrointestinal tract. ... Nerve growth factor (NGF), is a small secreted protein which induces the differentiation and survival of particular target neurons (nerve cells). ... Dopamine is a phenethylamine naturally produced by the human body. ...

The central nervous system (CNS) adapts to the presence of psychoactive drugs. Such adaptation commonly involves the readjustment of neuroreceptors to compensate for the acute pharmacological action of the medication. Desired drug effects may be mediated by such compensatory changes which may explain the delayed onset of therapeutic effect of antidepressants. This adaptation theory also explains why withdrawal symptoms and signs can occur on the discontinuation of such medications as clearance of drug can occur at a rate faster than the brain can readjust to the absence of medication. Hence, pharmacodynamic and pharmacokinetic factors contribute to the risk of a withdrawal syndrome. Pharmacodynamic factors explain why withdrawal syndromes are often a class issue and why the administration of a drug in the same class often relieves withdrawal symptoms. Formal studies have not characterized the relative risk. A diagram showing the CNS: 1. ... In biochemistry, a receptor is a protein on the cell membrane or within the cytoplasm or cell nucleus that binds to a specific molecule (a ligand), such as a neurotransmitter, hormone, or other substance, and initiates the cellular response to the ligand. ... Pharmacology (in Greek: pharmacon is drug, and logos is science) is the study of how chemical substances interfere with living systems. ... Pharmacodynamics is the study of the biochemical and physiological effects of drugs and the mechanisms of drug action and the relationship between drug concentration and effect. ... Pharmacokinetics is a branch of pharmacology dedicated to the study of the time course of substances and their relationship with an organism or system. ...

One theory purported by the Brain Imaging Center, McLean Hospital, Harvard Medical School, states that SSRI discontinuation syndrome is associated with a rostral anterior cingulate Cho/Cre metabolite ratio decrease that may reflect dynamics of rostral anterior cingulate cortex (ACC) function. Grays FIG. 727– Medial surface of left cerebral hemisphere. ...

The ACC appears to play a role in a wide variety of autonomic functions, such as regulating heart rate and blood pressure, and is vital to cognitive functions, such as reward anticipation, decision-making, empathy, and emotion. Neuroscientists indicate the dorsal anterior cingulate cortex is primarily related to rational cognition while the ventral is more related to emotional cognition.^[12] Anatomy and Physiology of the A.N.S. In contrast to the voluntary nervous system, the involuntary or autonomic nervous system is responsible for homeostasis, maintaining a relatively constant internal environment by controlling such involuntary functions as digestion, respiration, and metabolism, and by modulating energy needed to cope with stressful... Look up Cognition in Wiktionary, the free dictionary. ...

A separate study at the McLean Hospital and Department of Psychiatry, Harvard Medical School, demonstrated that changes in regional central blood volume (CBV) of left prefrontal cortex and left caudate nucleus correlate with the emergence of discontinuation symptoms and increased Hamilton Depression Rating Scale (HDRS) after interruption of paroxetine treatment. The findings supported the hypothesis that brain regions implicated in depression, with extensive serotonergic innervation, would exhibit changes in activity associated with emergence of symptoms following drug discontinuation. Cerebral blood volume (CBV) maps were obtained via dynamic susceptibility functional magnetic resonance imaging (fMRI).^[13] Look up cortex in Wiktionary, the free dictionary. ... Grays Fig. ... The Hamilton Depression Rating Scale is a 21-question multiple choice questionnaire which doctors may use to rate the severity of a patients depression. ... Functional magnetic resonance imaging (fMRI) is the use of MRI to measure the haemodynamic response related to neural activity in the brain or spinal cord of humans or other animals. ...

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

Another possible mechanism is by inhibition of dopaminergic neurotransmission.^[14] Dopamine is a phenethylamine naturally produced by the human body. ...

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 setraline (ranging approximately 10 hours) means that a single missed dose may cause withdrawal symptoms. The elimination half-life of a drug (or any xenobiotic agent) refers to the timecourse necessary for the quantity of the xenobiotic agent in the body (or plasma concentration) to be reduced to half of its original level through various elimination processes. ...

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

Treatment is dependent on the severity of the discontinuation reaction and whether or not further antidepressant treatment is warranted. In cases where further antidepressant treatment is required then the only step required is restarting the antidepressant; this is usually the case following patient noncompliance with the drug. If antidepressants are no longer required, treatment depends on symptom severity. Mild reactions may only require reassurance. Moderate cases may require symptom management, for example benzodiazepines can be used for insomnia. If symptoms are severe, or do not respond to symptom management, the antidepressant can be reinstated and then withdrawn more cautiously.^[15]

For severe withdrawals, many doctors have patients taper their medication no more than 5% per week, as to avoid a drastic drop in serotonergic activity. This slow taper can be done either by purchasing oral suspension versions of the drug (if available), cutting pills, or dissolving capsules of the medication in orange juice.^[16]

Tapering Regimen

A tapering regimen is not provided in manufacturers' package inserts. The optimum tapering regimen for each agent has yet to be determined by comparative clinical trials. From a review of the case reports (MEDLINE search from 1982 to May 1997), the following tapering schedules presented are suggested.^[17] It has been suggested that GoPubMed be merged into this article or section. ...

Suggested SSRI and SSNRI Tapering Schedule

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

Persisting adverse effects

Recent case reports describe four young men and women who experienced serious sexual dysfunction that continued to be symptomatic despite medication discontinuation years previously^[18][19].

Long term withdrawal syndromes outside of sexual dysfunction from SSRI's are not well documented, but reports are starting to be published. Symptoms can persist for months and include agitation, anxiety, akathesia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, crying spells or mood lability, overactivity or hyperactivity, depersonalization, decreased concentration, slowed thinking, confusion and memory/concentration difficulties. ^[20] For some patients in this condition, restarting the drug can cause intolerable side effects, meaning these symptoms have to be endured until they eventually subside.

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

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

Discontinuation of SNRIs

SNRIs affect both reuptake inhibition of serotonin and norepinephrine. They are considered the strongest of the SSRI family of drugs. The two mostly widely prescribed SNRIs are venlafaxine and duloxetine. Serotonin norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant used in the treatment of clinical depression and other affective disorders. ... Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal tract of animals including humans. ... Norepinephrine (INN) or noradrenaline (BAN) is a catecholamine and a phenethylamine with chemical formula C8H11NO3. ...

Discontinuation of Venlafaxine

Sudden discontinuation of venlafaxine has a high risk of causing potentially severe withdrawal symptoms. Even missing a single dose can cause symptoms of withdrawal.^[21][22] The high risk of withdrawal symptoms reflect venlafaxine's short half-life as well as its effect as a dual uptake inhibitor.^[15] Discontinuations have a tendency to be significantly stronger than the withdrawal effects of other antidepressants including the tricyclic antidepressants, but are similar in nature to those of SSRIs with short half-life such as paroxetine. Venlafaxine hydrochloride is a prescription antidepressant first introduced by Wyeth in 1993. ... Chemical structure of the tricyclic antidepressant amitriptyline Tricyclic antidepressants are a class of antidepressant drugs first used in the 1950s. ...

Symptoms of discontinuation are similar to other antidepressants including irritability, restlessness, headache, nausea, fatigue, excessive sweating, dysphoria, tremor, vertigo, irregularities in blood pressure, dizziness, visual and auditory hallucinations, feelings of abdominal distension, and paresthesia. Other non-specific mental symptoms may include impaired concentration, bizarre dreams, delirium, cataplexy, agitation, and worsening of depressive symptoms.^{[21][15][22][23][24][25][26]} Look up dysphoria in Wiktionary, the free dictionary. ... Paresthesia or paraesthesia (in British English) is a sensation of tingling, pricking, or numbness of a persons skin with no apparent long-term physical effect, more generally known as the feeling of pins and needles or of a limb being asleep. // Transient paresthesia is the temporary sensation of tingling... Cataplexy is a medical condition which often affects people who have narcolepsy, a disorder whose principal signs are EDS (Excessive Daytime Sleepiness), sleep attacks, and disturbed nighttime sleep. ...

Electric shock sensations have also been reported^[22][25] 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.^[27] Brain zaps, (proposed name: myalotinasis from Greek for brain + jolt) also known as the electric brain thing, brain shivers, brain shocks, battery head, blips, or brain spasms, are a fairly common and notorious withdrawal symptom experienced during discontinuation (or reduction of dose) of SSRI and SNRI antidepressant drugs. ... Neurons (also called nerve cells) are the primary cells of the 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. Wyeth-Ayerst is a large American pharmaceutical company. ...

Discontinuaton of Duloxetine

Eli Lilly The manufacturer of duloxetine - brand name Cymbalta - warns that "one should not suddenly stop taking this medicine, as this may cause withdrawal symptoms such as dizziness, pins and needles sensations, nausea, difficulty sleeping, intense dreams, headache, tremor, agitation or anxiety. Withdrawal symptoms are temporary and are not the same as addiction." One of the worlds largest corporations, Eli Lilly and Company (NYSE: LLY) is a global pharmaceutical company with headquarters in Indianapolis,Indiana, USA. A Fortune 500 corporation, the company had revenues of $12. ... Duloxetine hydrochloride (brand names: Cymbalta/Yentreve and in parts of Europe known as Xeristar or Ariclaim) is a drug that primarily targets major depressive disorders (MDD), pain related to diabetic peripheral neuropathy and in some countries stress urinary incontinence (SUI). ... Categories: Medicine stubs | Chemistry stubs | Serotonin-norepinephrine reuptake inhibitors ...

"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.^[28]

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.

In addition to being a potent dual uptake inhibitor, duloxetine is a systemic drug therapy that affects the body as a whole, and may implicate a tougher adjustment for the patient to discontinue treatment. Systemic Relating to, or affecting a particular body system; especially the nervous system. ...

Fluoxetine as Intervention in SSRI Discontinuation Syndrome

Many doctors advise patients who are suffering from SSRI discontinuation syndrome to use fluoxetine as a substitute for their current drug.^[29] Substituting fluoxetine in the final stages of SSRI discontinuation, or post discontinuation, provides a rate of reduction of antidepressant which can minimize or eradicate withdrawal symptoms in the patient. Fluoxetine migrates slowly from the brain to the blood. The active metabolite of fluoxetine remains a long time in the brain because it is lipophilic, with a biological half life of 4 to 8 days (the longest of any SSRI). Therefore the level of the drug in the body falls slowly at a rate to which the brain can adjust when the dosage is reduced. Fluoxetine is also available in a liquid formula, allowing the physician to titrate the drug with greater ease. This article or section does not cite its references or sources. ...

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.^[30]

• Intractable withdrawal from venlafaxine treated with fluoxetine was reported by WJ Giakas, JM Davis - Psychiatric Ann, 1997.

• Fluoxetine for clomipramine withdrawal symptoms was reported by Benazzi F - Am J Psychiatry, 1999. ^[31]

• Fluoxetine was indicated to cover serotonergic discontinuation syndromes for cessation of paroxetine associated with withdrawal or discontinuation symptoms. ^[32]

Clomipramine (brand-name Anafranil®) is a tricyclic antidepressant. ... Serotonergic means related to, capable of producing, altering, or releasing serotonin, a neurotransmitter, and can refer to the following classes of chemicals: Selective serotonin reuptake inhibitor - A common class of serotonergic antidepressants Noradrenergic and specific serotonergic antidepressant - Another class of serotonergic antidepressants serotonergic psychedelics - The serotonergic hallucinogenic drugs This is...

Neonatal Withdrawal

The FDA issued a warning on July 19, 2006 to nursing mothers on SSRIs must discuss treatment with their physicians. The United States Food and Drug Administration is the government agency responsible for regulating food, dietary supplements, drugs, cosmetics, medical devices, biologics and blood products in the United States. ...

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

SSRI withdrawal syndromes been documented in neonates. Investigators found that by November 2003, a total of 93 cases of SSRI use associated with either neonatal convulsions or withdrawal syndrome had been reported. Subsequently, the authors of a study published in The Lancet concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with psychiatric disorders.^[33] Lancet may refer to: A lancet is a medical instrument, similar to a scalpel but with a double-edged blade. ...

Controversy

See also: Biopsychiatry controversy and Biological psychiatry

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.^[34] The biopsychiatry controversy is an ongoing dispute over the scientific basis of biological psychiatry theory and practice. ... Biological psychiatry, or biopsychiatry is an approach to psychiatry that aims to understand mental disorder in terms of the biological function of the nervous system. ...

Much of the criticism stems from questions about the validity of claims that SSRIs work by 'correcting' chemical imbalances. Without accurately measuring patients' neurotransmitter levels to allow for continuous monitoring during treatment, it is impossible to know if one is correctly targeting a deficient neurotransmitter (i.e. correcting an imbalance), reaching a desirable level, or even introducing too much of a particular neurotransmitter. Thus it has been aruged 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.^[35] Chemical imbalance is a term sometimes used by drug companies [1] in the United States in advertising and consumer literature for psychoactive drugs after the deregulation of pharmaceutical advertising. ... Chemical structure of D-Aspartic Acid, a common Amino Acid neurotransmitter. ...

Most biopsychiatrists believe that, among other factors, the balance of neurotransmitters in the brain is a biological regulator of mental health. In this theory, emotions within a "normal" spectrum reflect a proper balance of neurochemicals, but abnormally extreme emotions, such as clinical depression, reflect an imbalance. Psychiatrists claim that medications regulate neurotransmitters and also claim they treat abnormal personalities by removing a neurochemical excess or replenishing a deficit (though the efficacy of antidepressants and antipsychotics is not undisputed ^[36]). On the other hand, Elliot Valenstein, a psychologist and neuroscientist, claims that the broad biochemical assertions and assumptions of mainstream psychiatry are not supported by evidence. ^[37] Chemical structure of D-Aspartic Acid, a common Amino Acid neurotransmitter. ... Italic text // ahh addiing sum spiice iin hurr`` For other uses, see Brain (disambiguation). ... Clinical depression (also called major depressive disorder, or unipolar depression when compared to bipolar disorder) is a state of intense sadness, melancholia or despair that has advanced to the point of being disruptive to an individuals social functioning and/or activities of daily living. ... An antidepressant is a medication used primarily in the treatment of clinical depression. ... The term antipsychotic is applied to a group of drugs used to treat psychosis. ...

Critics suggest mainstream psychiatry theory is influenced by pharmaceutical companies' sales and marketing departments. Richard Smith (former editor of the British Medical Journal) wrote about how the drug industry can subtly influence what is published in the scholarly literature. He said, "I must confess that it took me almost a quarter of a century editing for the BMJ to wake up to what was happening." ^[38] Richard Smith is the former editor of the British Medical Journal (BMJ) and chief executive of the BMJ Publishing group. ... The British Medical Journal (BMJ) is a medical journal published weekly in the United Kingdom by the British Medical Association (BMA)which published its first issue in 1845. ... Academic publishing describes a system of publishing that is necessary in order for academic scholars to review work and make it available for a wider audience. ...

One controversial critic of antidepressants, Peter Breggin, a physician who opposes the overuse of prescription medications to treat patients for mental health issues, predicted iatrogenic issues that SSRIs incur on a significant percentage of patients. Another prominent SSRI critic is David Healy. Peter R. Breggin is a controversial psychiatrist from the United States. ... An iatrogenic (pronounced , IPA) condition is a state of ill health or adverse effect caused by medical treatment, usually due to mistakes made in treatment. ... David Healy is an Irish psychiatrist who is currently Reader in Psychological Medicine at Cardiff University College of Medicine, Wales. ...

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

In both the U.S. and United Kingdom (UK) class action lawsuits have been brought against GlaxoSmithKline (GSK) for withdrawal symptoms of paroxetine (Paxil in US, Seroxat in UK) not listed in the manufacturer's medication insert. GlaxoSmithKline plc (LSE: GSK NYSE: GSK) is a British based pharmaceutical, biologicals, and healthcare company. ...

Summation

Many physicians prescribe SSRIs for patients off-label, and many are not diagnosed with conditions recognized in the Diagnostic and Statistical Manual of Mental Disorders (DSM) for which the drugs are indicated. Furthermore, the all too common practice of antidepressant prescriptions written after a brief consultation by general practice or family doctors who are not thoroughly informed of the significance of all the side effects or have the right monitoring system in place compounds the problem. The Diagnostic and Statistical Manual published by the American Psychiatric Association The poopDiagnostic and Statistical Manual of Mental Disorders (DSM), published by the American Psychiatric Association, is the handbook used most often in diagnosing mental disorders in the United States. ...

To facilitate proper diagnosis and avoid unnecessary therapeutic or diagnostic interventions, it is advised that all physicians who prescribe SSRIs should become familiar with the symptoms of SSRI discontinuation syndrome, in addition to hospital staff. The most appropriate approach to therapy for discontinuation syndrome involves educating physicians of the syndrome, and educating patients and reassuring them that this is a reversible condition, reinstating the original SSRI, or instituting a new SSRI, and further slowing the rate of tapering.

See also

• Neuropsychopharmacology
• Neuropharmacology
• Neurotoxicology
• Neuropsychotoxicology
• Pharmacology
• Psychoactive drug

Technical advancements in recent years have allowed progress toward the understanding of the brain and how drugs can be made to affect it. ... Neuropharmacology is the branch of health science concerned with the study of drugs on the nervous system. ... It has been suggested that Neurotoxicity be merged into this article or section. ... Neuropsychotoxicology is the subdiscipline of neurotoxicology concerned with the study of toxins or toxicants that have adverse effects on the mind, affecting behavior and/or neurological function. ... Pharmacology (in Greek: pharmakos (φάρμακον) meaning drug, and logos (λόγος) meaning science) is the study of how substances interact with living organisms to produce a change in function. ... A psychoactive drug or psychotropic substance is a chemical substance that acts primarily upon the central nervous system where it alters brain function, resulting in temporary changes in perception, mood, consciousness and behavior. ...

Footnotes