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Discontinuation symptoms systematically evaluated in patients taking duloxetine following abrupt discontinuation in MDD placebo-controlled clinical trials of up to 9-weeks duration, the following symptoms occurred at a rate greater than or equal to 2% and at a significantly higher rate in Cymbalta-treated patients compared to those discontinuing from placebo: dizziness; nausea; headache; paresthesia; vomiting; irritability; and nightmare.
Discontinuation symptoms systematically evaluated in patients taking duloxetine following abrupt discontinuation in MDD placebo-controlled clinical trials of up to 9-weeks duration, the following symptoms occurred at a rate greater than or equal to 2% and at a significantly higher rate in Cymbalta-treated patients compared to those discontinuing from placebo: dizziness; nausea; headache; paresthesia; vomiting; irritability; and nightmare.


⚫
Data obtained from 9 clinical trials assessing the efficacy and safety of duloxetine in the treatment of major depressive disorder (MDD) by Lilly Research found that patients with discontinuation-emergent adverse events (DEAEs) were reported by 44.3% of duloxetine patients, with an average of 2.4 DEAE's per patient. The report stated that abrupt discontinuation of duloxetine is associated with DEAE profiles similar to that seen with other selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. 35% of DEAE's lasted longer than one week. No follow up was published by Lilly stating the duration of DEAE's longer than one week ultimately persisted for.
In another trial by Detke and colleagues, discontinuation rates were more frequent in duloxetine-treated patients and the most frequent adverse events were nausea, dry mouth, dizziness, and constipation.

⚫
Data obtained from 9 clinical trials assessing the efficacy and safety of duloxetine in the treatment of major depressive disorder by Lilly Research found that patients with discontinuation-emergent adverse events (DEAEs) were reported by 44.3% of duloxetine patients, with an average of 2.4 DEAE's per patient. The report stated that abrupt discontinuation of duloxetine is associated with DEAE profiles similar to that seen with other selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. 35% of DEAE's lasted longer than one week. No follow up was published by Lilly stating the duration of DEAE's longer than one week ultimately persisted for.


Subsequently, Eli Lilly recommendeds that, "whenever possible, clinicians gradually reduce the dose no less than 2 weeks before discontinuation of duloxetine treatment." Tapering process may be moot for some patients, and they will still have discontinuation/withdrawal symptoms.
Subsequently, Eli Lilly recommendeds that, "whenever possible, clinicians gradually reduce the dose no less than 2 weeks before discontinuation of duloxetine treatment." 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.
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

Initial research on discontinuation/withdrawal syndrome attributes the syndrome to electrophysiological changes in the brain (particularly on the 5-HT receptor) and body (nerve growth factor) in the absence of duloxetine, as well as an over-excited immune system. The latter theory is due to duloxetine's immune suppressing effects.


==Fluoxetine as Intervention in SSRI Discontinuation Syndrome==
==Fluoxetine as Intervention in SSRI Discontinuation Syndrome==

Revision as of 17:20, 13 December 2006

SSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a condition that can occur following the interruption or discontinuation of regular SSRI or SNRI usage. The condition can begin between 24 hours to one week after discontinuation, depending on the half-life of the drug. Occasionally with Prozac, symptoms can take two weeks or more to emerge, owing to the drug's extremely long half-life.

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 withdrawal symptoms, as described by researchers.[1] Compared to the withdrawal symptoms of such drugs as opiates, alcohol, or cocaine, these reactions are quite different and frequently less significant, although the prescribing labels acknowledge the possibility of "intolerable" discontinuation reactions and some patients are never able to completely withdraw from SSRI drugs.

Double-blind controlled studies now indicate that 35-78% of patients who, after five weeks or more of treatment with the medication, abruptly stop certain antidepressants or titrate down in 10mg increments or more, will develop one or more of the discontinuation 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.

Despite the lack of a definition based on consensus criteria for the syndrome, patients who have disequilibrium, flulike symptoms, and sleep or sensory disturbances within 24 to 72 hours after discontinuing SSRI use are likely to be experiencing a discontinuation reaction. This is especially true if the symptoms cannot be ascribed to other causes and are alleviated by reintroduction of the medication.

List of SSRI's

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

Escitalopram is simply the left-handed s-enantiomer of the racemic citalopram. It had been introduced to the market just before the patent protection for citalopram had expired.

It is commonly thought that that the primary action of St. John's wort is as an MAOI.

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 pharmacokinetic properties rather than its effect on serotonin reuptake inhibition. That said, it does still share many properties of the typical SSRIs, especially the possibility of the 'discontinuation syndrome'.

Symptoms

Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated SSRIs. Just because a side effect is stated here, it does not mean that all people using one of these medicines will experience that or any side effect.

  • Increased sweating
  • Decreased appetite and weight loss
  • Rapid weight gain
  • Disturbances of the gut, such as nausea, constipation, diarrhea, indigestion, vomiting
  • Decreased sex drive or difficulty achieving orgasm
  • Taste disturbances
  • Difficulty passing urine
  • Increase in blood pressure or heart rate
  • Cold hands or feet

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.

These symptoms often resolve on reintroduction of the drug and cannot be explained as a remanifestation of the original disorder. To facilitate proper diagnosis and avoid unnecessary therapeutic or diagnostic interventions, all physicians who prescribe SSRIs should become familiar with these symptoms.

- Post SSRI Sexual Dysfunction (PSSD)[2] is an iatrogenic type of sexual dysfunction caused directly by the previous use of SSRIs. While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs. It may represent a specific subtype of SSRI discontinuation syndrome.

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

Mechanism

Antidepressant withdrawal effects do not indicate addiction in the strict medical sense, but are rather the results of the brain attempting to reach neurochemical stability after an abrupt change. These can often be minimized or avoided by tapering off of the medication over a period of weeks or months, although this is not always successful, especially for long-term users.

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

The ACC appears to play a role in a wide variety of autonomic functions, such as regulating heart rate and blood pressure, and is vital to cognitive functions, such as reward anticipation, decision-making, empathy, and emotion. Neuroscientists indicate the dorsal anterior cingulate cortex is primarily related to rational cognition while the ventral is more related to emotional cognition.[3]

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 magnetic resonance imaging.[4]

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 Prozac, to a shorter one, that taking their dose regularly becomes much more important. Patients taking Prozac can often miss several doses without noticing any discomfort, but the shorter halflife of other SSRIs such as Paxil or Zoloft (20 - 26 hours) means that a single missed dose may cause withdrawal symptoms.

The condition may be avoided by either recommencing the original, and/or lesser dose of the SSRI, or 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.[5]

Persisting adverse effects

Some patients, especially those who have used the medicines for a long period of time or at a higher dosage, can experience persistent adverse effects on discontinuing an SSRI, which last well beyond the initial period of discontinuation syndrome. These can vary from mild (poor short-term memory, poor concentration, tinnitus) to more severe (akathisia, tachycardia, depersonalization, sexual dysfunction, extreme anxiety in excess of pre-treatment levels). Little research has been done into the phenomenon, so no reliable scientific analysis is limited.

Most patients complaining of persisting post-SSRI effects experience significant improvement within two years, although some symptoms have been known to persist indefinitely.

One case reported a 26-year-old male who experienced genital anaesthesia during sertraline treatment and continued to be symptomatic despite medication discontinuation 6 years previously.[6]

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.[7] The high risk of withdrawal symptoms may reflect venlafaxine's short half-life.[5] Missing even a single dose can induce discontinuation effects in some patients.[8] 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 such as Paroxetine (Paxil® or Seroxat®).

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.[7][5][8][9][10][11][12]

Electric shock sensations have also been reported[8][11] with patients describing the symptoms as "brain shivers". It has been suggested the sensations may represent an alteration of neuronal activity in the central nervous system.[13]

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). In some venlafaxine withdrawal cases, successful discontinuation was eventually achieved by the addition of fluoxetine, which was later discontinued itself without difficulty.

One early and 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 drugs like Effexor incur on a significant percentage of patients.

Discontinuaton of Duloxetine

The manufacturer of duloxetine - brand name cymbalta - Eli Lilly, 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.

Discontinuation symptoms systematically evaluated in patients taking duloxetine following abrupt discontinuation in MDD placebo-controlled clinical trials of up to 9-weeks duration, the following symptoms occurred at a rate greater than or equal to 2% and at a significantly higher rate in Cymbalta-treated patients compared to those discontinuing from placebo: dizziness; nausea; headache; paresthesia; vomiting; irritability; and nightmare.

Data obtained from 9 clinical trials assessing the efficacy and safety of duloxetine in the treatment of major depressive disorder (MDD) by Lilly Research found that patients with discontinuation-emergent adverse events (DEAEs) were reported by 44.3% of duloxetine patients, with an average of 2.4 DEAE's per patient. The report stated that abrupt discontinuation of duloxetine is associated with DEAE profiles similar to that seen with other selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. 35% of DEAE's lasted longer than one week. No follow up was published by Lilly stating the duration of DEAE's longer than one week ultimately persisted for.

Subsequently, Eli Lilly recommendeds that, "whenever possible, clinicians gradually reduce the dose no less than 2 weeks before discontinuation of duloxetine treatment." 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

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.[14] 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. This is primarily because of the long half-life of fluoxetine (4 days and 8 days for its intermediary). Therefore the level of the drug in the body falls slowly at a rate to which the brain can adjust when a capsule is eliminated from the dose taken.

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 Apr;156(4):661-2. Links

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.[15] Much of the criticism stems from questions about the validity of claims that SSRIs work by 'correcting' chemical imbalances. Without tools to accurately measure neurotransmitter levels and 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.[16] One possible mechanism is by inhibition of dopaminergic neurotransmission.[17]

Most SSRIs are indicated for Major Depressive Disorder (MDD) and their efficacy and safety has not been shown by clinical studies or FDA-approved for long term use. Still many physicians prescribe SSRIs for patients not diagnosed with (MMD) or other Diagnostic and Statistical Manual of Mental Disorders (DSM) that they the drugs are indicated for.

Many physicians, unaware of the potential severity of discontinuation syndrome, do not get informed consent at the time of initial prescription from the patient, 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.

To facilitate proper diagnosis and avoid unnecessary therapeutic or diagnostic interventions, all physicians who prescribe SSRIs should become familiar with these symptoms, in additional 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, instituting a new SSRI, and further slowing the rate of tapering.

Footnotes

  1. ^ Tamam L, Ozpoyraz N. "Selective serotonin reuptake inhibitor discontinuation syndrome: a review". Adv Ther. 19 (1): 17–26. PMID 12008858.
  2. ^ Bahrick A. Post SSRI Sexual Dysfunction. American Society for the Advancement of Pharmacotherapy Tablet 2006; 7:2-10.
  3. ^ Kaufman MJ, Henry ME, Frederick B, Hennen J, Villafuerte RA, Stoddard EP, Schmidt ME, Cohen BM, Renshwa PF (2003). "Selective serotonin reuptake inhibitor discontinuation syndrome is associated with a rostral anterior cingulate choline metabolite decrease: a proton magnetic resonance spectroscopic imaging study". Biol Psychiatry. 54 (5): 534=539. PMID 12946882.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Kaufman MJ, Henry ME, Frederick B, Hennen J, Michelson D Vukovic AJ, Stoddard EP, Schmidt ME, Cohen BM, Renshwa PF (2003). "Selective serotonin reuptake inhibitor discontinuation syndrome is associated with a rostral anterior cingulate choline metabolite decrease: a proton magnetic resonance spectroscopic imaging study". Biol Psychiatry. 53 (1): 100–5. PMID 12513950.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ a b c Haddad P (2001). "Antidepressant discontinuation syndromes". Drug Saf. 24 (3): 183–97. PMID 11347722.
  6. ^ Bolton (2006). "Genital anaesthesia persisting six years after sertraline discontinuation". J Sex Marital Ther. 4: e327. PMID 16709553.
  7. ^ a b Fava M, Mulroy R, Alpert J, Nierenberg A, Rosenbaum J (1997). "Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine". Am J Psychiatry. 154 (12): 1760–2. PMID 9396960.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ a b c Parker G, Blennerhassett J (1998). "Withdrawal reactions associated with venlafaxine". Aust N Z J Psychiatry. 32 (2): 291–4. PMID 9588310.
  9. ^ van Noorden M, Vergouwen A, Koerselman G (2002). "[Delirium during withdrawal of venlafaxine]". Ned Tijdschr Geneeskd. 146 (26): 1236–7. PMID 12132141.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Nissen C, Feige B, Nofzinger E, Riemann D, Berger M, Voderholzer U (2005). "Transient narcolepsy-cataplexy syndrome after discontinuation of the antidepressant venlafaxine". J Sleep Res. 14 (2): 207–8. PMID 15910521.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ a b Baboolal N (2004). "Venlafaxine withdrawal syndrome: report of seven cases in Trinidad". J Clin Psychopharmacol. 24 (2): 229–31. PMID 15206672.
  12. ^ Reeves R, Mack J, Beddingfield J (2003). "Shock-like sensations during venlafaxine withdrawal". Pharmacotherapy. 23 (5): 678–81. PMID 12741444.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Benazzi F (1998). "SSSRI discontinuation syndrome treated with fluoxetine". Int J Geriatr Pyschiatry. 13 (6): 421–2. PMID 9658279.
  14. ^ Lacasse JR, Leo J. Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature. PLoS Medicine 2005;2:e392.
  15. ^ Moncrieff J, Cohen D. Do Antidepressants Cure or Create Abnormal Brain States? PLoS Medicine 2006;3:e240.
  16. ^ Damsa C, Bumb A, Bianchi-Demicheli F, Vidailhet P, Sterck R, Andreoli A, Beyenburg S. "Dopamine-dependent" side effects of selective serotonin reuptake inhibitors: a clinical review. J Clin Psychiatry. 2004;65:1064-8. PMID 15323590.

External links

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