Law Project for
              Psychiatric Rights

Antidepressants Research
compiled by
Grace E. Jackson, MD in writing

Rethinking Psychiatric Drugs: A Guide to Informed Consent

Fava G:  Do antidepressants and antianxiety drugs increase chronicity in affective disorders?  Psychotherapy and Psychosomatics  1994; 61: 125-131.

 Presents important questions for researchers and clinicians, raising possibility that antidepressants and benzodiazepines / barbiturates may induce biological changes which lead to permanent symptoms, albeit less severe than original in some cases.  Fava is defender of “drugs + therapy,” and criticizes the benzodiazepine critics whom he calls “the narrow-minded damnation chorus.”  Nonetheless, he acknowledges the results of research showing that chronic administration of xanax (alprazolam) is inferior to exposure therapy, even when alprazolam is COMBINED with exposure therapy.  In a study conducted in Toronto, patients given the benzodiazepine for panic disorder with agoraphobia had long term outcomes that were worse then psychotherapy alone.   Similarly, Fava mentions the findings of the Pittsburgh Study of Maintenance Therapies in recurrent depression, which suggest that patients maintained on low doses of antidepressants become unable to withdraw from drug treatment after three years.  Fava raises questions about whether drugs therefore may be causing more harm than good, by inducing chemical changes which increase the sensitivity of individuals to the behavioral features of anxiety or depression.   Benzodiazepines may be sensitizing the brain to anxiety by inducing downregulation of the GABA A receptor, the putative mechanism responsible for panic attacks.  Fava implies that there may be similar adaptations occurring in the brain, which lead to permanent residual symptoms of depression.

 El-Mallakh RS, Waltrip C, Peters C: Can Long Term Antidepressant Use Be Depressogenic?  Journal of Clinical Psychiatry  1999; 60 (4): 263.

 Three clinicians in Louisville, KY have written a letter to the Editor at the Journal of Clinical Psychiatry, responding to an article (Rothschild and Byrne)  about loss of antidepressant efficacy despite maintenance therapy with antidepressants.  In the letter, the authors acknowledge the long-noted tendency of antidepressants to induce mania and/or rapid cycling.  They emphasize the tendency of long term effects of drug treatments to vary widely from acute effects.  A possible mechanism that may be responsible for the medication-related induction of chronic depressive symptoms lies in anatomic changes: changes in neuronal number, or changes in synaptic number.  The authors cite several studies demonstrating these changes in animals treated with antidepressants.  Either kind of change might render human subjects more susceptible to depressive symptoms over time.  In other words, it is possible that antidepressants  -- just like neuroleptics – induce structural changes in the brain which make symptoms refractory to treatment.

Byrne SE, Rothschild AJ: Loss of Antidepressant Efficacy During Maintenance Therapy: Possible Mechanisms and Treatments.  Journal of Clinical Psychiatry  1998; 59 (6): 279-288.

 Authors look at frequency with which antidepressant medication responders begin to experience return of depressive symptoms, despite the continuation (maintenance) phase of drug treatment.  The authors have performed a search of Medline, reviewing  13   double-blind, placebo controlled studies involving treatment with antidepressants for at least six months, between 1966 and 1997.   They report a frequency of relapsing/recurring symptoms while taking medication of   9 – 57%.  They  also acknowledge that the Hamilton Rating Scale for depression, used in most studies, probably underestimates the frequency of  “relapse” during treatment due to the fact that it emphasizes vegetative features.  The authors acknowledge that many more patients (more than 60%) who are continuing their treatment with antidepressant medication experience the return of, or worsening, of depressed mood, apathy, and fatigue.  They suggest a number of possible reasons for these effects, ultimately concluding that it may be necessary to “raise doses” or  “add more medications” to compensate for the decreasing efficacy of antidepressants.

 Fava GA: Can Long Term Treatment With Antidepressant Drugs Worsen the Course of Depression ?  Journal of Clinical Psychiatry  2003; 64 (2): 123-133.

 Author looks at possibility that antidepressants may worse the course of depression in the long term.  He reviews the existing literature (Medline search) to find articles describing the phenomena of tolerance, sensitization, or switching associated with antidepressant therapy.  He concludes that continued drug treatment may “recruit” processes in the brain that oppose the initial acute effects of drug treatment, and which increase vulnerability to relapse during or after the continuation of medication.  The author suggests that “antidepressants are crucial in the treatment of major depressive episodes,” but he suggests that they possibly worsen the overall course of the disorder they are intended to relieve.  Concerned about the paradoxical effects of pharmacotherapy (long term treatment makes some patients worse), he suggests that “further study is needed.”

Brugha TS, Bebbington PE, MacCarthy B, Sturt E, Wykes T: Antidepressants may not assist recovery in practice: a naturalistic prospective survey.  Acta Psychiatrica Scandinavica  1992; 86: 5-11.

 In a study of 130 patients referred to Maudsley hospital for further evaluation of depression, 119 were reassessed after a 4 month period of treatment.  All patients in the study were interviewed within six months of the onset of their first depressive episode, or within six months of a recurrent depressive episode.  Of the 119 patients who were successfully followed up at four months, 13 were admitted to an inpatient unit of the hospital; 3 were admitted to a day hospital program; and all others were continued either in outpatient psychiatric care (54),  the care of their GP (29),  or  no care (19 decided to pursue no further treatment).  Results at follow-up showed a consistent trend (although not robust) for a “worse outcome in those on drug treatment.”  Patients receiving drug treatment in the study were no more ill (no worse) in the study than those who did not receive it.  44 patients in the study were not on medication at the time of the first interview.  16 of them were placed on medication – 30% of these individuals recovered, compared to 50% (28 patients) who remained medication free.  Overall rates of recovery were found to be 71% of untreated (not medicated)  vs.  61% of those on medication.

Fava GA: Potential Sensitising Effects of Antidepressant Drugs on Depression.  CNS Drugs 1999; 12 (4): 247-256.

 Fava presents evidence to support the hypothesis that antidepressant drugs may sensitise the brain and worsen the long term outcome.  He suggests clinical findings demonstrating unfavorable long term outcomes when patients are treated pharmacologically.  Fava includes the examples of antidepressant-induced depression, anxiety, mania, and/or rapid cycling in some patients; the occurrence of tolerance to the effects of drugs during long term treatment; the existence of withdrawal syndromes following the discontinuation of antidepressant drugs; and the onset of resistance when some patients are later rechallenged with the same antidepressant drug.   Fava supports the use of antidepressants as a treatment for depression, but he believes that the use of these drugs might need to be modified (limited) in order to prevent the deleterious consequences of  sensitization.  He recommends a cost-benefit appraisal of antidepressants, in order to avoid using them for “prophylaxis,” for minor symptoms, or for anxiety.   Fava worries that the current trend of long-term antidepressant administration may be counter-productive, due to the induction of brain changes which contribute to diminishing drug response over time.

Salin-Pascual RJ, Galicia-Polo L, Drucker-Colin R:  Sleep Changes After 4 Consecutive Days of Venlafaxine Administration in Normal Volunteers.  Journal of Clinical Psychiatry  1997; 58 (8): 348-350. 

 The authors present the results of a study involving 8 normal volunteers who were given venlafaxine (a combined noreinephrine / serotonin reuptake inhibitor) for four consecutive nights.   They studied the quality of sleep in these subjects for two nights prior to the initiation of drug treatment, followed by four nights consecutive nights during drug therapy.   The volunteers were assessed in a sleep laboratory, where the following measures were obtained: EEG, electrooculogram, electromyogram, EKG, and thermistor measurements (nose and mouth).  Findings were significant for reductions in sleep stages I and III.  REM sleep was reduced after the first dose of venlafaxine, and was completely suppressed by the fourth night.  Six of the eight volunteers experienced periodic limb movements of sleep (PLMS).  Authors speculate that sleep disturbances noted in this study may have been caused by abrupt rise in aminergic neurotransmitters (norepinephrine, serotonin, dopamine), which are thought to suppress REM sleep.

Clemes SR, Dement WC: Effect of REM Sleep Deprivation On Psychological Functioning.  Journal of Nervous and Mental Disease  1967; 144 (6): 485-491.

 Investigators examined six college students (age 18-20) during a period of six nights of REM sleep deprivation, followed one week later by six nights of non-REM sleep deprivation (or vice versa).  Subjects were tested with certain neuropsychological instruments on days seven and fourteen, in order to see if changes in sleep patterns were associated with any significant changes in cognition or behaviors.  Results suggested that REM deprivation may cause reductions in ego control, as reflected in this study by changes in critical thinking skills (less concern about matching concepts to physical outlines in the Holtzman inkblot).  These changes were not found to be caused by fatigue or sleepiness.  Subjects were also evaluated for changes in  ‘reality testing’  after REM sleep deprivation, with marked changes noted in one subject.   Responses to the TAT (thematic apperception test) suggested an increase in “intensity of need” and “intensity of feeling” (emotionality) following REM sleep deprivation.   The authors of the study suggest that REM sleep deprivation stimulates in humans – as in animals – an increase in certain instinctive drives.

Vasar V, Appelberg B, Rimon R, Selvaratnam:  The effect of fluoxetine on sleep: a longitudinal, double-blind polysomnographic study of healthy volunteers.  International Clinical Psychopharmacology  1994; 9: 203-206.

 Investigators administered fluoxetine (prozac) and placebo in a randomized, double blind trial involving 12 healthy volunteers.  Subjects had polygraphic (sleep) recordings performed at home twice before and once after receiving medication for six days.  Fluoxetine was associated with a significant reduction in total minutes of REM sleep, percentage of sleep spent in REM, and an increase in REM latency.  Actual sleep time was not affected.  The Symptom Check List-90 (SCL-90) was also completed before and after treatment with fluoxetine.  The 90 items on the check list include symptom dimensions including: somatization, obsessive-compulsive items, interpersonal sensitivity, depression, anxiety, anger-hostility, paranoia, and psychoticism.  A significant change (decrease) was found only in the subscale on “interpersonal sensitivity,” which could be interpreted either as a reduction in “rejection sensitivity” or, alternatively, as an increase in feelings of indifference towards the thoughts or opinions of others.  The authors conclude that their polygraphic findings are consistent with the findings of other investigators, noting that most antidepressants suppress REM sleep.

Winkelman JW, James L: Serotonergic antidepressants are associated with REM sleep without atonia.  Sleep  2004; 27 (2): 317-321.

 Authors report the results of a study involving a sleep lab investigation of 15 subjects receiving a serotonergic antidepressant (prozac, paxil, celexa, Zoloft, effexor) vs. 15 age –matched controls not taking any such medication.  Subjects were recruited from a polysmonography database at Sleep Health Centers in Newton Center, MA.  The investigators performed a chart review, analyzing clinical and sleep data for subjects referred to their center for the evaluation of a sleep disorder.  None of the subjects included in the study were diagnosed with sleep apnea, which was the primary reason for referral.  The investigators performed a retrospective analysis of the sleep studies, concentrating on EMG tone (muscle tone) changes during REM sleep in individuals receiving chronic treatment with serotonergic antidepressants.  Interestingly, these were subjects who did not have any complaints of abnormal behavior during sleep.  Findings were significant for increased submental activity during REM among subjects taking antidepressants, with 13% of the subjects in this study exceeding Gagnon’s criteria for REM sleep behavior disorder (RBD); 53% exceeding Eisensehr’s criteria for RBD.  The authors of this study conclude that the clinical status of REM sleep without atonia – as seen in their patient sample – remains ambiguous. Even so, they express their concerns that REM sleep without atonia may be an early stage of RBD.   They suggest that there are substantial potential public health implications of REM sleep abnormalities in individuals taking serotonergic antidepressants, particularly in the context of more than 10 million people in the US alone taking these drugs.

 [Note: the significance of RBD is as follows: during normal REM sleep, the muscle tone of the body is inhibited or  “turned off” so that the sleeper does not act out, physically, the scenes of a dream.  RBD is a form of “wakeful dreaming” during which a person is technically asleep, but moving – it can lead to the enactment of violent or otherwise injurious behaviors, as the person literally acts out his or her dreams.]

Wallace WAH, Balsitis M, Harrison BJ: Male breast neoplasia in association with selective serotonin reuptake inhibitor therapy: a report of three cases.  European Journal of Surgical Oncology  2001; 27: 429-431.

 The authors are surgeons in the UK, who describe three cases of carcinoma of the breast in male patients, all of whom had exposure to SSRIs (serotonin reuptake inhibitors).  Carcinoma of the male breast is an extremely rare form of breast cancer, occurring in less than 1% of all cases.  This paper describes three male patients who presented with neoplastic or pre-neoplastic breast disease, all of whom were prescribed SSRIs prior to their surgical consultations.  The authors of this article suggest that SSRI-related breast cancer may be more easily assessed in male populations, due to the absence of complex physiological changes in the male breast throughout life.  The authors also discuss several epidemiological studies revealing increased risks of breast cancer in women using SSRIs (2-7 fold higher risk, relative to women not using SSRIs).

Cotterchio M, Kreiger N, Darlington G, Steingart A: Antidepressant Medication Use and Breast Cancer Risk.  American Journal of Epidemiology  2000; 151 (10: 951-957. 

 Authors note that 30% of all newly diagnosed cancers in females are breast cancers, and that 19% of all female cancer-related deaths are due to breast cancer.  At the same time, they note an increase of breast cancer incidence of 20-25% between the early 1970s and the early 1990s.  Recognizing the increasing use of antidepressant medications in women, and noting the connection between antidepressants and breast cancer risk in animals, the authors performed a case-control study using the Ontario (Canada) Cancer Registry.  They identified breast cancer cases in women age 25-74 yrs, diagnosed between 1995 and 1996.  Population controls were identified using property assessment rolls.  Subjects were asked about antidepressant use, with subjects excluded if they had reported less than 2 weeks’ duration of treatment; or if they had taken antidepressant medication only in the six month period immediately prior to their breast cancer diagnosis.   The use of tricyclic antidepressants for greater than two years was associated with a two-fold elevation in breast cancer risk.  The use of paroxetine (paxil) was associated with a seven-fold elevation in breast cancer risk.  There was no association between duration of SSRI use and breast cancer risk.  Possible mechanisms for the risks in this study include: stimulation (by paroxetine) of prolactin secretion, which has been implicated in the etiology of breast cancer; inhibition of the P450 2D6 enzyme (which may lead to a reduced clearance of carcinogens and estrogen by the liver); and/or stimulation of benign proliferative breast disease, which may be precursor to breast cancer.   The authors conclude that there remains a paucity of epidemiologic studies in this area, and they express concerns about the long-term use of antidepressants. 

 Preda A, MacLean RW, Mazure CM, Bowers MB, Jr:  Antidepressant-Associated Mania and Psychosis Resulting in Psychiatric Admissions.  Journal of Clinical Psychiatry  2001; 62 (1): 30-33.

 The authors report their findings of a retrospective chart review of all admissions to their university-based hospital psychiatric unit over a 14 month period.   They reviewed the records of 533 consecutive admissions to the inpatient service at Yale-New Haven Hospital between 1/97 and 2/98.   Patients included in the study were subjects experiencing the onset or exacerbation of mania and/or psychosis as the primary reason for admission; antidepressant use at the time of admission; recent initiation (within 16 weeks) of antidepressant therapy; and rapid improvement following the discontinuation of antidepressant therapy (along with the addition of a neuroleptic or mood stabilizer, if indicated).  Excluded from the study were all individuals severe personality disorders; concurrent substance use disorders; stable medication regimens at admission; or patients who had recently undergone reductions in neuroleptic dose.  Despite this conservative approach (with numerous exclusions), the investigators discovered that 8% of the patients admitted to the inpatient unit fit the profile of anti-depressant induced mania or psychosis.  The authors conclude that the rate of admissions due to antidepressant-associated behavioral effects remains significant.  

[Note:  The findings of this study were consistent with an earlier study by the same authors, in which they found that 11% of the consecutive admissions to their inpatient unit over a period of six months were associated with antidepressant therapy. 

Given the fact that these Yale studies focused only upon patients whose symptoms were severe enough to require hospitalization, it is quite likely that the actual rates of antidepressant-induced mania and/or psychosis are higher than these studies suggest.] 

Leo RJ: Movement Disorders Associated With the Serotonin Selective Reuptake Inhibitors.  Journal of Clinical Psychiatry  1996; 57 (10): 449-454.

 The author reviews the medical literature (Medline and bibliographies) for case reports of SSRI-induced movement disorders.  Acknowledging the limitations of adverse event reporting systems (namely, that all such cases are spontaneously reported), Leo concedes that the prevalence of SSRI-associated motoric effects cannot be generated from the published literature.  Nonetheless, he inventories the 71 case reports of de novo motor symptoms arising in patients after the initiation of SSRIs.  Among the movement disorders noted are: akathisia (45% of cases); dystonia (28%); parkinsonism (14%); tardive dyskinesia-like movements (11%); tremors (10%).  Pathophysiologic mechanisms thought to be responsible for these effects include: inhibitory effects of serotonin fibers upon extrapyramidal neurons; SSRI inhibition of dopamine synthesis (and other catecholamines) in the forebrain, striatum, and/or hippocampus; interaction between serotonergic neurons and GABA or cholinergic pathways; or SSRI-induction of hypersensitivity in postsynaptic dopamine receptors.  The author concludes that further controlled studies comparing movement disorders among SSRI- and placebo treated patients are required.

Ditto, KE: SSRI Discontinuation syndrome: Awareness as an approach to prevention. Postgraduate Medicine  2003; 114 (2): 79-84.

 The author highlights the symptoms which characterize the SSRI discontinuation syndrome, noting a frequency of occurrence as high as 25% in patients who stop taking those agents abruptly.  Ditto offers Malcolm Lader’s definition of a withdrawal syndrome:

“well-defined syndrome with predictable onset, duration, and offset of action containing psychological and bodily symptoms not previously complained of by patients.” 

The article calls attention to the fact that SSRI discontinuation symptoms can begin within 1-3 days of abruptly stopping (or tapering) SSRI therapy, and can continue for several weeks if not treated.  Features include anxiety, crying spells, insomnia, irritability, nausea, vomiting, dizziness, headache, paresthesias, dystonia or tremor, chills, fatigue, muscle pain, or runny nose.   The author suggests that SSRI discontinuation syndrome occurs most commonly in individuals who have taken such drugs for less than 6-8 weeks.   The article discusses differential diagnoses, noting that SSRI discontinuation syndrome is easily overlooked (not considered or recognized), easily prevented (patient education, slow tapers,  avoidance of missed or expired doses), and easily managed (resumption of previous drug, substitution of longer-acting drug, or initiation of slow taper).

Liu BA, Mittmann N, Knowles SR, Shear NH: Hyponatremia and the Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with the Use of Selective Serotonin Reuptake Inhibitors: A Review of Spontaneous Reports.  Canadian Medical Assocation Journal  1996; 155 (5): 519-527.

 The authors conducted a review of  SSRI-associated SIADH as reported in the medical literature (30 published cases) and unpublished case reports held by a variety of authorities (e.g., pharmaceutical industry, FDA, Health Protection Branch of Ontario, the World Health Organization).  SIADH (syndrome of inappropriate antidiuretic hormone) is a potentially life-threatening disorder which can result in dangerously low levels of sodium, seizures, coma, and death.  The authors of this study reviewed published reports

Between 1980 and 1995.  83% of the published cases, and 74% of the unpublished cases, involved patients age 65 or older.  75% of the cases occurred within 30 days of initating therapy.  The exact mechanism of SSRI-associated SIADH remains unknown, but possible causes include:  effects on dopamine, as neuroleptics have been known to facilitate ADH secretion; effects on norepinephrine (stimulation of ADH via alpha-2 receptors); 5HT2 or 5HT1C receptor mediation of ADH release; peripheral effects on the renal medulla; or the re-setting of the body’s osmostat, resulting in a lower threshold for the secretion of ADH.  The authors conclude that SIADH may be a significant health risk related to the use of SSRIs in older patients.  However, they acknowledge the fact that further research is needed in order to determine the incidence of this adverse effect, and in order to establish the relative risk of SSRI-induced hyponatremia among different (all) age groups.

Weintrob N, Cohen D, Klipper-Aurbach Y,  Zadik Z, Dickerman Z:  Decreased Growth During Therapy With Selective Serotonin Reuptake Inhibitors. Archives of Pediatric and Adolescent Medicine   2002; 156: 696-701.

 Authors report on 4 patients (age 12 to 14) treated with SSRIs who all experienced significant growth suppression when their pubertal growth spurt was expected.  Three of the patients demonstrated a decreased growth hormone response to a clonidine stimulation test; two of the patients showed diminished response to both clonidine and glucagon stimulation tests; and one subject displayed a decreased 24-hour secretion of growth hormone which normalized immediately upon the cessation of SSRI therapy.  The authors conclude that a decrease in growth rate may occur during SSRI therapy, and that the expanding use of these drugs – particularly, in young age groups – warrants larger studies to investigate their effects upon growth and growth hormone secretion.

Birmes P, Coppin D, Schmitt L, Lauque D: Serotonin syndrome: a brief review.  CMAJ  2003; 168 (11): 1439-1442.

 The authors describe two short case reports involving serotonin syndrome.  The article is a review of serotonin syndrome, outlining the major and minor symptoms, their cause, and their management.  Serotonin syndrome is a potentially fatal reaction to any of a variety of medications that increase serotonergic tone in the central nervous system.  Symptoms include behavioral changes (insomnia, agitation), neurological effects (confusion, obtundation, hyperreflexia, myoclonus, tremors, seizures, coma), and autonomic dysregulation (hyperhidrosis, rapid heart rate, elevated BP, fever).  Other symptoms include GI distress (nausea, vomiting, diarrhea); changes in white blood cells; and elevated creatine kinase.   The authors propose a variety of possible cellular mechanisms leading to these symptoms: overstimulation of serotonin (5HT1A) receptors in central gray nuclei and medulla; overstimulation of 5HT2 receptors;  inhibition of SSRI metabolism by other drugs; excessive synthesis or release of serotonin.  Treatment involves immediate discontinuation of SSRIs, IV fluids to prevent risk of myoglobinuria (and kidney failure), and other stabilizing measures as needed (cooling bed, mechanical ventilation, anticonvulsants, anxiolytics, antihypertensive agents).  Some studies have suggested benefits with the use of beta-blockers, which may reduce symptoms through their concomitant antagonism of 5HT1A receptors.  Other possible treatments include serotonin antagonists (such as cyproheptadine) and/or neuroleptics (such as chlorpromazine, ziprasidone) which block 5HT1A receptors.  Authors emphasize importance of patient education, limitation of polypharmacy, and use of “drug holidays.”

Carbone JR: The Neuroleptic Malignant and Serotonin Syndromes.  Emergency Medicine Clinics of North America  2000; 18 (2): 317-325.

 Author discusses NMS (neuroleptic malignant syndrome) as a rare, idiosyncratic reaction to antipsychotic therapies.  Incidence of NMS is estimated to be 1%.  Article discusses the features of NMS, its pathophysiology, diagnosis, and management.  The author then moves on to discuss the “serotonin syndrome”: a toxic effect of SSRIs (and/or other drugs) believed to arise from the over-stimulation of 5HT1A receptors in the brain and spinal cord.  Features include mental status changes, neuromuscular and autonomic dysregulation.  Patients with NMS are more apt to experience high fevers, swallowing difficulty, incontinence, drooling.  Patients with SS (serotonin syndrome) are more likely to present with GI (gastrointestinal) side effects, such as diarrhea or vomiting.  In addition, SS patients are more likely to demonstrate shocklike contractions in muscles (myoclonus), hyperreflexia, and ataxia.  Treatment involves immediate removal of the offending agent(s).  Use of dopamine antagonists is recommended with reservation by this author, due to the fact that NMS would be made worse by neuroleptic therapy (and NMS can easily be confused for SS).  The use of serotonin antagonists has been recommended by some.  Propranolol (beta-blocker, recommended for its theoretical role in blocking 5HT receptors) has been associated with at least one death in a patient with SS.   The mainstays of treatment for SS include removal of the offending agent, supportive care (IV fluids), judicious use of benzodiazepines, and intensive monitoring (e.g., ICU admission).

Martin TG: Serotonin Syndrome.  Annals of Emergency Medicine  1996; 28 (5): 520-526.

 SSRIs have largely replaced tricyclic antidpressants (TCAs) in the USA.  The author proposes that the consequences of SSRI-poisonings (overdose) have tended to be less serious than TCA overdoses.  However, Martin suggests that the incidence of adverse effects and drug interactions is greater.  He describes the characteristic features of serotonin syndrome (mental status changes, autonomic dysfunction, neuromuscular abnormalities); its most common precipitants, differential diagnoses, and treatment.  Author makes important points: bromocriptine and dantrolene (two treatments commonly recommended for NMS) may actually worsen SS by increasing 5HT levels in the brain.  Similarly, the use of serotonin antagonists (methysergide, cyproheptadine) and beta-blockers (propranolol) are recommended only with caution.  At least one patient developed SS and died from it, despite treatment with propranolol at the time that the serotonin syndrome emerged.  The author therefore recommends careful supportive care: use of cooling measures, sedatives, anticonvulsants, antihypertensives, mechanical ventilation and paralytics (to reduce excessive muscle activity and hyperthermia), if required.  While serontonin syndrome can be mild to moderate in severity and self-limited (resolving in 24-72 hours), some cases can be severe, lethal, and longer lasting (with some residual symptoms persisting for weeks).


 A quick word about REM sleep, and why drug-induced REM suppression is concerning.  Researchers discovered that many depressed patients appeared to have an increase in REM sleep compared to non-depressed individuals.  They also noted the impact of antidepressant drugs upon REM sleep.   As a result, psychiatrists began to experiment with REM sleep deprivation as a potential treatment for depression back in the 1970s and 1980s.   This practice fell out of favor, due to poor reproducibility of results, mixed findings, and short-acting benefits.  More recently, studies investigating REM sleep and its association with depression have suggested that REM sleep decreases as individuals recover from depression.  Since most of the antidepressants suppress REM sleep chronically,  the continuation of such treatments past the point of symptom remission may actually go too far,  ultimately contributing to mood and cognitive disruption. 

REM sleep is more than the “phase of sleep” in which 90% of human dreaming occurs.  REM sleep is thought to be essential for learning and memory.  The suppression of REM sleep may therefore impair the acquisition and retrieval of new information, the formation of long term memory, the maintenance of procedural skills, and the overall capacity for cognitive flexibility.