ANTIDEPRESSANTS

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Trends in the prescribing of antidepressant pharmacotherapy: office-based visits, 1990-1995.
Sclar DA. et al.
Clin Ther 1998 Jul-Aug;20(4):871-84; 870.

The results of this study show that the number of office visits resulting in prescription of an antidepressant drug increased from 16,534,268 in 1990 to 28,664,796 in 1995, a 73.4% increase. A diagnosis of depression was documented in 6.7% of the U.S. population in 1990, and in 7.1% in 1995, a 16.4% increase. The large increase in number of prescriptions, not matched by a similar increase in the prevalence of depression, suggests that the criteria for prescribing antidepressant medications have loosened during the study period. A variation in rates of prescribing of different class of drugs was also noticed, with a decline in use of tricyclic antidepressants (from 42% to 25%), and an increase in use of selective serotonin reuptake inhibitors (from 37% to 65%).


Association between selective serotonin reuptake inhibitors & upper gastrointestinal bleeding
population based case-control study.
de Abajo, FJ, García Rodríguez LA, Montero D.
BMJ 1999;319:1106-1109 ( 23 October ).

The results of this study show that users of the antidepressants selective serotonin reuptake inhibitors (SSRIs) have a significantly increased risk of upper gastrointestinal (GI) bleeding, compared to nonusers. The study was conducted on 1651 patients hospitalized with upper GI bleeding, and 10,000 matched controls. Use of SSRIs was associated with a 3-fold increased risk of bleeding, compared to nonuse. The incidence of this complication was estimated at 1every 8,000 prescriptions. Combined use of SSRIs and aspirin was associated with a 7-fold increased risk of GI hemorrhage, and combined use of SSRIs and non-steroidal anti-inflammatory drugs resulted in a 15.6-fold increased risk. The authors emphasize that the large increase in risk of GI hemorrhage observed in their study could have important public health implications due to the frequent use of both classes of drugs in industrialized countries.


Hemorrhagic syndromes related to selective serotonin reuptake inhibitor (SSRI) antidepressants.
Seven case reports and review of the literature. French.
Nelva A, Guy C, Tardy-Poncet B, Beyens MN, Ratrema M, Benedetti C, Ollagnier M.
Rev Med Interne 2000 Feb;21(2):152-60.

The results of this study suggest that intake of the antidepressants selective serotonin reuptake inhibitors is associated with an increased risk of developing hemorrhagic syndromes. This adverse effect is under-recognized and under-reported, and may be due to a decrease in concentration of platelet serotonin, leading to platelet dysfunction.


Antidepressant Medication Use and Breast Cancer Risk.
Cotterchio M, Kreiger N, Darlington G, and Steingart A.
Am J Epidemiol 2000;151:951-57.

The results of this study indicate that women who take antidepressants are at significantly higher risk of developing breast cancer, compared to the general population. The association between antidepressant drugs and breast cancer first emerged from animal and epidemiological data. This case-control study, conducted to further test the hypothesis, found that users of selective serotonin reuptake inhibitors (SSRIs) and tryciclic antidepressants have a 7- and 2-fold increased risk of breast cancer, respectively, compared to nonusers. The finding of a large increase in risk of breast cancer in users of SSRIs may have public health implications owing to the high prevalence of use of this class of drugs.


Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology of serotonergic nerve terminals using serotonin immunohistochemistry.
Kalia M, et al.
Brain Res 2000 Mar 6;858(1):92-105.

The results of this study indicate that short-term exposure to selective serotonin reuptake inhibitors (SSRIs) results in changes of rat brain cells, which resemble those induced by the recreational drug Ecstasy. SSRIs work by increasing the concentration of serotonin in the brain through inhibition of their re-uptake by brain cells. Their mode of action is similar to that of the recreational drug Ecstasy, which also increases the concentration of serotonin at the receptor site through a double action of inhibited reuptake and stimulated secretion from brain cells. While Ecstasy-induced brain damage has been well demonstrated in both animal and human studies, there are no data on the effects of SSRIs on brain cells. This study documented that, after only 4 days of intake of SSRIs, rat brain cells underwent morphological changes characterized by swelling and acquisition of a corkscrew shape, indicative of occurred damage. These findings indicate that SSRIs, the most commonly prescribed class of antidepressant drugs, cause damage in animal brain cells, after only 4 days of exposure. More studies on humans are needed, before these drugs can be considered safe.


Discontinuation symptoms and psychotropic drugs
Young, A. and Haddad P.
Lancet 2000; 355: 1181 - 1190.

This letter emphasizes that 35% to 78% of individuals who take the antidepressants selective reuptake inhibitors (SSRIs) for several months, experience, upon abrupt treatment interruption, physical and psychological symptoms such as: changes in mood, affect, appetite and sleep, dizziness, fatigue, anxiety, agitation, nausea, headache, and sensory disturbance. The symptoms are so typical that the clinical entity "SSRI discontinuation syndrome" is now widely accepted, after its existence had been negated for several years following the introduction of SSRIs on the market. Symptoms are usually mild and short-term, but occasionally can be severe and long lasting. They have often been interpreted as a sign of relapse into depression, leading to re-institution of treatment. The authors propose that all new psychotropic drugs be tested in double-blind placebo-controlled studies lasting several weeks beyond the actual drug trial, in order to properly monitor adverse reactions that may occur only upon discontinuation of treatment.


Hormonal markers of stress response following interruption of selective serotonin reuptake inhibitor treatment.
Michelson D, et al.
Psychoneuroendocrinology 2000 Feb;25(2):169-77.

The results of this study show that following abrupt interruption of treatment with selective serotonin reuptake inhibitors patients develop signs of activation of a stress response, as shown by significantly increased plasma levels of IGF-1 and heart rate.


Antidepressant discontinuation reactions.
Haddad P, Lejoyeux M, and Young A.
BMJ 1998;316:1105-1106 ( 11 April ).

This article reports on the frequency and nature of adverse reactions occurring upon discontinuation of antidepressant treatment. It explains that the existence of discontinuation reactions is often unrecognized by clinicians and that the extent of their occurrence is largely unknown because very few studies have ever addressed this issue. Discontinuation reactions usually start after few days of interruption of antidepressant treatment, and may consist of nausea, diarrhea, abdominal pain, insomnia, nightmares, headaches, lethargy, anxiety, and irritability. With selective serotonin-reuptake inhibitors, withdrawal is more commonly associated with symptoms such as dizziness, paraesthesia, numbness, and electric shock-like sensations. Results of a double blind placebo controlled study have shown that adverse reactions occur in 35% of patients after discontinuation of a 12-week treatment with the serotonin reuptake inhibitor paroxetine. Such reactions usually resolve within one day to three weeks, but occasionally they can be more severe and persist chronically, causing substantial morbidity.


Discontinuation symptoms after treatment with serotonin reuptake inhibitors
a literature review.
Zajecka J, et al.
J Clin Psychiatry 1997 Jul;58(7):291-7.

The results of this study indicate that discontinuation of selective serotonin-reuptake inhibitor therapy is associated with the development of a cluster of symptoms including dizziness, light-headedness, insomnia, fatigue, anxiety, nausea, headache, and sensory disturbance. These symptoms may last up to three weeks after interruption of treatment, and may be relieved by restarting antidepressant therapy (!).


Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline, and venlafaxine.
Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR, Bagby RM.
J Clin Psychiatry 2000 Apr;61(4):276-81.

The results of this study indicate that 30%-70% of patients who take the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline experience sexual dysfunction as a side effect of treatment. Impairment in drive and/or desire occurs more frequently in men than women, while impairment in level of arousal and orgasm is experienced at similar rates by both sexes. These data indicate that the majority of patients treated with SSRIs experience sexual dysfunction. The low rates of this complication reported in previous studies were due to underreporting and was not confirmed in subsequent trials.


Sexual dysfunction induced by serotonin reuptake antidepressants.
Labbate LA, Grimes J, Hines A, Oleshansky MA, Arana GW.
J Sex Marital Ther 1998 Jan-Mar;24(1):3-12.

The results of this study show that the antidepressants selective serotonin reuptake inhibitors negatively affect sexual functios. The study was conducted on 61 individuals who took these drugs for at least two months. Both men and women experienced a significant worsening of quality of orgasm after 1 and 2 months of treatment, compared to baseline. Women reported failure to achieve an orgasm significantly more often than men, while both sexes experienced prolongation of time to orgasm induction after 1, 2, and 3 months of treatment, compared to baseline.


Incidence of sexual dysfunction in healthy volunteers on fluvoxamine therapy.
Nafziger AN, et al.
J Clin Psychiatry 1999 Mar;60(3):187-90.

The results of this study show that 35% of healthy volunteer who took the antidepressant fluvoxamine developed, after 4 weeks of treatment, sexual dysfunction.


Adverse reactions of selective serotonin reuptake inhibitors
reports from a spontaneous reporting system.
Spigset O.
Drug Saf 1999 Mar;20(3):277-87.

This study evaluated 1202 spontaneous reports on 1861 adverse reactions to selective serotonin reuptake inhibitors (SSRIs), and found that 22.4% of such reports consisted of neurological disturbances, 20% of psychiatric disorders, and 18% of gastrointestinal symptoms. The elderly were particularly susceptible to Parkinsonism, confusion, hallucinations, and hypotension, while younger patients experienced more frequently hematological, endocrine, and sexual dysfunction. Akathisia and aggression occurred more frequently in men than women.


A survey of antidepressant drug use in Parkinson's disease. Parkinson Study Group.
Richard IH, et al.
Neurology 1997 Oct;49(4):1168-70.

The results of this study indicate that approximately 26% of patients with Parkinson's disease (PD) are given antidepressant medications, which consist, in over half of the cases, of serotonin reuptake inhibitors (SSRIs). Forty-three percent of physicians of the Parkinson Study Group showed concern that use of SSRIs might induce worsening of motor function in PD patients, and 37% of physicians had at least one patient in which they believed such aggravation occurred.


Prenatal exposure to fluoxetine (Prozac) produces site-specific & age-dependent alterations in brain serotonin transporters in rat progeny
Evidence from autoradiographic studies.
Cabrera-Vera TM, Battaglia G.
J Pharmacol Exp Ther 1998 Sep;286(3):1474-81.

The results of this study show that prenatal exposure to the selective serotonin reuptake inhibitor fluoxetine (Prozac) induces changes in the density of brain serotonin transporters in rats, which are particularly evident in regions of the limbic system, such as the hypothalamus, hippocampus and amygdala. These data indicate that fluoxetine alters brain function in rats exposed to the drug while in uterus.


Pregnancy outcome following first-trimester exposure to fluoxetine.
Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Sihn S, et al.
JAMA 1993 May 5;269(17):2246-8.

The results of this study show that women who use the antidepressant fluoxetine (Prozac) in the first trimester of pregnancy have approximately a 2-fold increased risk of miscarriage, compared to nonusers.


Birth outcomes in pregnant women taking fluoxetine.
Chambers CD, et al.
N Engl J Med, 335(14):1010-5 1996 Oct 3.

This study evaluated pregnancy outcome of women who took the antidepressant fluoxetine (a serotonin uptake inhibitor) while expecting, and compared it to that of women who did not take the drug. In infants exposed to the drug, the incidence of three or more minor anomalies was 15.5% vs. 6.5% in controls. Infants exposed to fluoxetine during the third trimester had, compared to those exposed only during the first and second trimester, reduced birth weight and length, an almost 5-fold increased risk of premature delivery, a 2.6-fold increased risk of being admitted to special-care nurseries, and an almost 9-fold increased risk of experiencing respiratory difficulties, cyanosis on feeding, and jitteriness.


Antidepressants and suicidal risk.
Muller-Oerlinghausen B, Berghofer A.
J Clin Psychiatry 1999;60 Suppl 2:94-9; discussion 111-6.

This article emphasizes that selective serotonin reuptake inhibitors and other non-lithium antidepressants may increase the risk of suicide in certain patients by inducing akathisia (a condition characterized by restlessness and psychomotor agitation and associated with self-destructive impulses) and by liberating suppressed energies that may be used to act upon suicidal thoughts.


Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia.
Rothschild AJ. et al.
J Clin Psychiatry, 52(12):491-3 1991 Dec.

This article describes three cases of attempt suicide after induction of akathisia in patients on fluoxetine therapy. When re-exposed to the drug, all three patients re-developed akathisia and precipitated in suicidal thoughts, strongly suggesting a relation of causality between drug exposure and suicidal impulse.


Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability.
Song F. et al.
BMJ 1993 Mar 13;306(6879):683-7.

This study presents the results of a meta-analysis of 63 randomized controlled studies comparing the efficacy of selective serotonin reuptake inhibitors (SSRIs) to that of tricyclic antidepressants as first line treatment for depression. The analysis revealed that SSRIs are no more effective than tryciclics in the management of depression. Dropouts rate were similar for both class of drugs, but slightly more patients reported side effects as a reason for dropping out in the tryciclic group compared to those in the SSRI group (18.8% v 15.4%). The authors concluded that "Routine use of selective serotonin reuptake inhibitors as the first line treatment of depressive illness may greatly increase cost with only questionable benefit". This study is important since it shows that SSRIs are not significantly better than classic antidepressant drugs, in spite of advertising campaigns claiming the superiority of SSRIs in the treatment of depression due to their excellent safety records. The underreporting of SSRI-related adverse reactions is also partly responsible for the vast increase in prescribing rates of these drugs.


Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients.
Cohn CK. et al.
J Clin Psychiatry, 51 Suppl B():28-33 1990 Dec.

In this study, 241 elderly individuals suffering from depression were randomized to receive an 8-week treatment with either amitriptyline (a tricyclic antidepressant) or sertraline (a serotonin uptake inhibitor). Over 30% of patients in the sertraline group and 35% in the amitriptyline group withdrew from the study because of drug-related side effects or laboratory abnormalities.


The cost of antidepressant drug therapy failure: a study of antidepressant use patterns in a Medicaid population.
McCombs JS, et al.
J Clin Psychiatry, 51 Suppl():60-9; discussion 70-1 1990 Jun.

The results of this study, conducted on a cohort of 2344 patients with major depressive disorders on antidepressant medications, show that only in 3.5% of patients the pattern of use of antidepressant was indicative of successful treatment. In 12.6 of patients, pattern of antidepressant use suggested treatment failure. In the remaining 84% of cases the efficacy of treatment could not be clearly classified.


The adequacy of reporting randomized, controlled trials in the evaluation of antidepressants.
Streiner DL, et al.
Can J Psychiatry, 43(10):1026-30 1998 Dec.

This study examined the statistical and methodological validity of 69 randomized control trials that compared the efficacy of two antidepressant drugs with that of placebo. Criteria scores were defined as minimal and ideal. Zero percent of the studies met all of the ideal criteria for reporting clinical trials. Only 9 of 69 articles met the minimal criteria to be included in metaanalytical studies. These data indicate that the quality of the majority of studies on antidepressant drugs is extremely poor.


Hyponatremia in relation to treatment with antidepressants:
A survey of reports in the World Health Organization database for spontaneous reporting of adverse drug reactions.
Spigset O, et al.
Pharmacotherapy 1997 Mar-Apr;17(2):348-52.

The results of this study show that from 1968 to 1993, 668 cases of antidepressant-related hyponatremia were spontaneously reported to the World Health Organization. In over half of the patients, the reaction occurred within two weeks of starting antidepressant treatment.


Relative mortality from overdose of antidepressants.
Henry JA, et al.
BMJ, 310(6974):221-4 1995 Jan 28.

This study reports on the case of 1606 deaths from antidepressant toxicity, occurring in the period from 1987 to1992. Over 80% of these deaths were associated to amitriptyline and dothiepin use.


Antidepressant-treated patients in ambulatory care. Mortality during a nine-year period after first treatment.
Bingefors K. et al.
Br J Psychiatry, 169(5):647-54 1996 Nov.

The results of this study show that, in individuals over 65 years of age, treatment with antidepressant is significantly associated with increased risk of long-term mortality, especially from cardiovascular causes.


QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients.
Reilly, J G. et al.
Lancet 2000; 355: 1048 - 1052.

The results of this study show that use of psychotropic drugs is associated with a significantly increased risk of heart arrhythmias. The study was conducted on 495 psychiatric patients and 101 healthy individuals who served as control. As a marker for increased risk of arrhythmias the authors used the lengthening of the QT interval on the electrocardiogram. Eight percent of patients receiving psychiatric drugs had prolonged QT interval, which poses them at risk of cardiac arrhythmias. The risk of having an abnormal QT interval in patients taking tricyclic antidepressants and the antipsychotic drugs thioridazine, and droperidol was increased by 4.4-, 5.5-, and 6.7-folds, respectively, compared to non-users. The risk increased with increasing doses of drugs, and was increased by more than 8 times in users of very high doses. These findings may explain some cases of sudden unexplained death occurring in patients taking psychotropic drugs, as this type of death has been linked to cardiac rhythm abnormalities.


Relative mortality from overdose of antidepressants
Henry JA, et al.
BMJ 1995;310:221-224 (28 January).

The results of this study show that for every million prescriptions written for antidepressant drugs, approximately 30 people die from overdose. Tricyclic drugs are associated with the highest incidence of death (34 deaths per million prescriptions), and selective serotonin reuptake inhibitors with the lowest (2 deaths per million prescription).


Imipramine overdose complicated by toxic megacolon.
Ross JP, et al.
Am Surg, 64(3):242-4 1998 Mar.

This article emphasizes that tricyclic antidepressants are responsible for approximately 20 to 25% of drug overdoses leading to hospitalization. Death occurs primarily from cardiovascular complications. Respiratory disturbances, urinary retention, constipation, and intestinal obstruction are common signs of toxicity. Less frequent complications include: pancreatitis, intestinal perforation, and gangrene of the large intestine.


Cardiotoxic side effects associated with tricyclic antidepressant overdose.
Keis NA.
AACN Clin Issues Crit Care Nurs, 3(1):226-32 1992 Feb.

This article emphasizes that intake of excessive doses of tricyclic antidepressants is associated with a significant risk of cardiotoxicity, especially during the first 24 hours from the overdose.


PSYCHOTROPIC DRUGS


"Psychotropic drugs" is a term that refers to drugs that have an effect on the psychological function, including antidepressants, antipsychotics or neuroleptics, anti-anxiety drugs, and hallucinogens. 


QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients
Reilly JG. et al.
Lancet 2000; 355: 1048 - 1052.

The results of this study show that use of psychotropic drugs is associated with a significantly increased risk of heart arrhythmias. The study was conducted on 495 psychiatric patients and 101 healthy individuals who served as control. As a marker for increased risk of arrhythmias the authors used the lengthening of the QT interval on the electrocardiogram. Eight percent of patients receiving psychiatric drugs had prolonged QT interval, which poses them at risk of cardiac arrhythmias. The risk of having an abnormal QT interval in patients taking tricyclic antidepressants and the antipsychotic drugs thioridazine, and droperidol was increased by 4.4-, 5.5-, and 6.7-folds, respectively, compared to non-users. The risk increased with increasing doses of drugs, and was increased by more than 8 times in users of very high doses. These findings may explain some cases of sudden unexplained death occurring in patients taking psychotropic drugs, as this type of death has been linked to cardiac rhythm abnormalities.


Dopamine-antagonistic, anticholinergic, and GABAergic effects on declarative and procedural memory functions.
Rammsayer TH, Rodewald S, Groh D
Brain Res Cogn Brain Res. 2000 Jan;9(1):61-71.
The results of this study show that the psychotropic drugs haloperidol and midazolam (a benzodiazepine used for sedation) significantly impair memory functions in healthy individuals. The study was conducted on 80 healthy volunteers who were randomly assigned to receive haloperidol, midazolam, scopolamine, or placebo. Adverse effects on immediate and delayed word recall tests were observed with all three drugs, but were more pronounced in individuals taking midazolam. All drugs provoked severe impairment on object recognition tests, and these effects were particularly strong in individuals receiving midazolam. The results of this study indicate that use of these drugs is associated with significant memory-related problems in healthy individuals.


A comparison of the effects of olanzapine, haloperidol and placebo on cognitive and psychomotor functions in healthy elderly volunteers.
Beuzen JN, Taylor N, Wesnes K, Wood A.
J Psychopharmacol (Oxf) 1999;13(2):152-8.

The results of this study show that the antipsychotic drug haloperidol produces significant cognitive and psychomotor impairment in elderly individuals, and these effects don't seem to improve with treatment. The study was conducted on 14 healthy elderly individuals who were randomly assigned to receive haloperidol, olanzapine (a new antipsuchotic drug), or placebo for 4 days. On day 1 of treatment, significant impairment in attention, memory, and motor control was observed in both groups receiving antipshycotic drugs. On day 4 of treatment, the cognitive and psychomotor deficits were attenuated in patients who took olanzapine, (indicating adaptation to these side effects), but had worsened in patients taking haloperidol. These data indicate that patients taking haloperidol may be experiencing significant deterioration of cognitive and motor skills from the drug. These powerful adverse effects must be taken in consideration when prescribing haloperidol to elderly individuals, as the drug may precipitate their overall health status and may render them unsuitable for independent living. Since other antipsychotic drugs don't share the same persistency of effects, haloperidol use should be replaced with safer alternatives.


Effects of haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers.
Peretti CS, Danion JM, Kauffmann-Muller F, Grange D, Patat A, Rosenzweig P.
Psychopharmacology (Berl). 1997 Jun;131(4):329-38.

The results of this study show that intake of haloperidol is associated with impaired cognitive functions in healthy individuals. The study was conducted on 60 healthy individuals who were randomized to receive haloperidol, amisulpride (a drug used in the treatment of depression and dysthymia), or placebo. Those who received haloperidol showed the greatest deficits in higher cognitive functions as evaluated through a battery of tests performed immediately after and some time after drug administration, while those who received amisulpride demonstrated cognitive slowing only at tests performed at distance from drug intake.


Psychomotor, Cognitive, extrapyramidal, and affective functions of healthy volunteers during treatment with an atypical (amisulpride) and a classic (haloperidol) antipsychotic.
Ramaekers JG, et al.
J Clin Psychopharmacol 1999 Jun;19(3):209-21.

The results of this study show that haloperidol significantly impairs cognitive and motor performance in healthy individuals. The study was conducted on 21 healthy volunteer who were randomly assigned to receive the atypical neuroleptic amisulpride, the classic neuroleptic haloperidol, or placebo, for 5 consecutive days. Significant cognitive and psychomotor deficits were observed at day 5 of treatment in individuals taking amisulpride and haloperidol. Additionally, practically every individual who took haloperidol exhibited extrapiramidal symptoms ranging from akatisia (restlessness of movements, an urge to move about constantly, often associated with anxiety and agitation) to acute dystonia (sustained abnormal postures or muscle spasms), and mental disturbances. These data indicate a high rate of severe adverse effects associated with neuroleptic intake. Interestingly, several of the adverse effects of haloperidol resemble symptoms found in schizophrenic patients, thus raising the question of whether they are due to the disease or to the treatment.


Managing antipsychotic-induced acute and chronic akathisia.
Miller CH, Fleischhacker WW.
Drug Saf 2000 Jan;22(1):73-81.

This article emphasizes that 5% to 37% of patients treated with antipsychotic drugs develops akathisia, a condition characterized by a feeling of restlessness accompanied by anxiety, agitation, and an urge to move about that leads patients to continuously rock while sitting or standing, to lift their feet as if marching on the spot and to cross and uncross their legs while sitting. Since currently there is no satisfactory treatment for this complication, the only remedy is to prevent its occurrence by reducing the intake of drugs, or switching to safer antipsychotic drugs.


Antipsychotic-induced life-threatening 'esophageal dyskinesia'.
Horiguchi J et al.
Int Clin Psychopharmacol 1999 Mar;14(2):123-7.

This article describes a potentially fatal adverse reaction to antipsychotic drugs, esophageal dyskinesia, consisting of abnormal movements affecting the lower portion of the pharynx and the upper portion of the esophagus. A case of a patient who died from asphyxiation of food is reported.


Effects of the clozapine national registry system on incidence of deaths related to agranulocytosis.
Honigfeld G.
Psychiatr Serv, 47(1):52-6 1996 Jan.

Clozapine is an antipsychotic drug with a high potential of inducing white blood cell suppression, and is administered only to patients whose weekly blood tests show no evidence of toxicity. From its release in 1990 until December 1994, 382 cases of agranulocytosis and 12 related deaths have been identified through a national patient registry maintained by the drug manufacturer. From results of clinical research performed prior to the release of the drug in the market, the expected number of cases of agranulocytosis and death was 995 and 149, respectively, raising the question of whether such a drug should have been approved in the first place.


A survey of sudden death associated with the use of antipsychotic or antidepressant drugs: 49 cases in Finland.
Mehtonen OP; Aranko K; M¨alkonen L; Vapaatalo H.
Acta Psychiatr Scand, 84(1):58-64 1991 Jul.

The antipsychotic class of drugs phenothiazines causes disturbances of the cardiac rhythm, and while their use has been associated with the occurrence of sudden death, a causal link has not been clearly demonstrated. This study shows that in 46 of 49 cases of sudden death reported in users of antipsychotic or antidepressant drugs, individuals were taking therapeutic doses of phenothiazines, which consisted of the drug thioridazine in over half the cases. The high representation of this class of drugs in individuals with sudden death is indicative of a causal association.


Assessment of EPS and tardive dyskinesia in clinical trials.
Collaborative Working Group on Clinical Trial Evaluations.
J Clin Psychiatry 1998;59 Suppl 12:23-7.

This article explains that approximately 50%-75% of individuals who take conventional antipshycotic drugs develop acute extrapyramidal symptoms (EPS) such as akathisia, dystonia and parkinsonism. Although the incidence of such symptoms is less frequent with the new antipsychotic drugs, the authors still caution to use them at doses below the EPS-producing levels until more data on their long-term effects are available.


Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk factors, and association with tardive dyskinesia.
Muscettola G, et al.
J Clin Psychopharmacol 1999 Jun;19(3):203-8.

This study evaluated the prevalence of signs of extrapyramidal syndrome (EPS) (akathisia, dystonia and parkinsonism) in a cohort of 1,559 patients treated with anti-psychotic drugs. EPS was present in approximately 30% of patients, with 65% of these patients presenting with signs of parkinsonism such as rigidity, tremors and slowness of movements. These data indicate a high rate of severe and disabling adverse reactions associated with neuroleptic use.


Intermittent neuroleptic treatment and risk for tardive dyskinesia: Curacao Extrapyramidal Syndromes Study III.
van Harten PN, et al.
Am J Psychiatry 1998 Apr;155(4):565-7.

The results of this study, conducted on a cohort of patients with a history of antipsychotic drug use of more than 3 months, show that the incidence of tardive diskinesia increases by 3-folds in patients who had 3 or more treatment interruptions, compared to those who had 2 or less breaks in drug therapy.


Incidence of tardive dyskinesia in early stages of low-dose treatment with typical neuroleptics in older patients.
Jeste DV, et al.
Am J Psychiatry 1999 Feb;156(2):309-11.

This study evaluated the incidence of tardive dyskinesia (a syndrome characterized by potentially irreversible, involuntary abnormal movements usually of the trunk and face, associated with use of antipsychotic drugs) in a cohort of 307 outpatients over 45 year of age treated with low-dose antipsychotic drugs. In patients who had not used this type of drugs in the past, the incidence of tardive dyskinesia was 3.4% after 1 month and 6% after 2 months of use. After 1 year, the syndrome developed approximately in 25% of patients, and in 37% of those who had a history of antipsychotic drug use of over 30 days.


Prospective study of tardive dyskinesia in the elderly: rates and risk factors.
Woerner MG, et al.
Am J Psychiatry 1998 Nov;155(11):1521-8.

The results of this study, conducted on a cohort of 261 patients on antipsychotic drugs, show that after 1, 2, and 3 years of cumulative treatment, 25%, 34%, and 53% of patients who started taking the drugs at age 55 or above developed tardive dyskinesia.


Incidence and risk factors for severe tardive dyskinesia in older patients.
Caligiuri MP, et al.
Br J Psychiatry 1997 Aug;171:148-53.
The results of this study show that after 1, 2, and 3 years of treatment with antipsychotic drugs, the incidence of severe tardive diskinesia in middle-aged and elderly individuals is 2.5%, 12% and 23%, respectively. The authors concluded affirming, "Conventional neuroleptics may be prescribed to older patients only when necessary and at the lowest effective dosage".


Transient and intermittent oral dyskinesia appearing in a young woman ten days after neuroleptic treatment.
Tawara Y, et al.
Clin Neuropharmacol 1997 Apr;20(2):175-8.

This article reports on the case of a 22-year-old woman initiated on antipsychotic drugs who developed severe extrapiramidal signs and tardive diskinesia lasting for 6 days, after only 9 days of treatment.


Neuroleptic drug exposure and treatment of parkinsonism in the elderly
a case-control study.
Avorn J, Bohn RL, Mogun H, Gurwitz JH, Monane M, Everitt D, Walker A.
Am J Med 1995 Jul;99(1):48-54.

The results of this study show that elderly patients who take antipsychotic drugs have a significant increased risk of developing symptoms of Parkinson's disease requiring initiation of pharmacological treatment. The study was conducted on a cohort of 3,512 patients aged 65 and older who received a new prescription for the treatment of Parkinson's disease and a similar number of controls without symptoms of parkinsonism. Users of neuroleptic drugs had a 5.4-fold increased risk of being treated for parkinsonism, compared to nonusers. Of note, users of neuroleptic drugs also had an over two-fold increased risk of receiving a drug with indications for idiopathic Parkinson's disease and not appropriate in individuals with drug-induced parkinsonism. The authors estimated that 37% of all prescriptions for the treatment of Parkinson's disease are due to neuroleptic drug use. In 71% of patients neuroleptic treatment was not discontinued in spite of the occurrence of parkinsonian symptoms. These data indicate that extrapyramidal symptoms of parkinsonism are a frequent complication of neuroleptic treatment. Physicians however, often fail to recognize that these symptoms are drug-related, as shown by the high rate of inappropriate prescribing of drugs that are not indicated for drug-induced parkinsonism, resulting in inappropriate management of the condition and failure of optimization of treatment regimens.


Drug-induced cognition disorders in the elderly: incidence, prevention and management.
Gray SL, Lai KV, Larson EB.
Drug Saf 1999 Aug;21(2):101-22.

This article highlights that elderly individuals are particularly at risk of developing drug-related delirium and dementia. Although practically every drug has the potential of worsening cognitive function in the elderly, those more commonly implicated are benzodiazepines, opioids, anticholinergics, and tricyclic antidepressants. The risk is particularly high in elderly frail individuals who are taking several medications at once, such that a careful evaluation should always be conducted to exclude the possibility of drug-related cognitive impairment in this age group.


Increased morbidity and mortality related to asthma among asthmatic patients who use major tranquillisers.
Joseph KS, et al.
BMJ 1996;312:79-81 (13 January).

The results of this study show that use of neuroleptic drugs in asthmatic patients with psychosis is associated with a 3.2-fold increased risk of death or near-death from asthma, compared to nonuse.


Association of venous thromboembolism and clozapine.
Staffan Hägg, Olav Spigset, Torbjörn G Söderström.
Lancet 2000; 355: 1155 - 1156.

The results of this study show that the antipsychotic drug clozapine is associated with a significantly increased risk of death from venous thromboembolism. The researchers evaluated cases of deep venous thrombosis and pulmonary embolism that occurred in individuals treated with clozapine, reported to the Swedish Adverse Reactions Advisory Committee from April 1989 through March 2000. Of the 12 patients who experienced venous thromboembolism, 5 died (42%). Median age of patients was 38 years. Only one had known risk factors for thromboembolism (contraceptive use). Sixty-seven percent of the cases occurred during the first 3 months of clozapine treatment. Overall, from 20,000 to 70,000 Swedish patients take clozapine, indicating that the risk of this complication is at least 1 per 2-6,000 treated patients. The actual risk, however, is likely to be higher, in view of the fact that reporting of adverse events is spontaneous (not mandatory), such that a substantial number of cases may be missed due to under-reporting.


Myocarditis and cardiomyopathy associated with clozapine.
Jens G Kilian, Kristin Kerr, Christopher Lawrence, David S Celermajer.
Lancet 1999; 354: 1841-45.

The results of this study show that individuals taking the anti-psychotic drug clozapine have a 1,000-2,000-fold increased risk of death from myocarditis, compared to non-users. The study was conducted after two young, physically healthy patients died unexpectedly soon after initiation of treatment. The authors investigated the risk of adverse cardiovascular effects by searching for cases of myocarditis and cardiomyopathy in the Australian Adverse Reaction Committee register, a voluntary reporting system. They found 15 reports of myocarditis and 8 of cardiomyopathy. Six patients died, 5 from myocarditis, and 1 from cardiomyopathy. All cases of myocarditis occurred within 3 weeks of initiation of treatment, whether cardiomyopathy occurred up to 3 years after initiation of treatment. From 1993 to 1999, 8,000 patients were started on clozapine in Australia. Among these 8,000 patients, a minimum of 23 cases of myocarditis and cardiomyopathy occurred, including 6 deaths. The number of patients who suffered these complications may, however be higher, since reporting of adverse events is not mandatory. Extrapolation of this data indicates that approximately 1 in 500 young individuals who are treated with clozapine for schizophrenia will have fatal and nonfatal myocarditis in the first month of treatment. These estimates are conservative, due to likely underreporting. Since myocarditis is a very rare cause of death worldwide (approximately 4 deaths per 1,000,000 individuals), these figures represent a 1000-2000 increased risk of death from the disease in patients taking clozapine, compared to the general population. In addition, users of clozapine have a 5-fold increased risk of cardiomyopathy, compared to non-users. This article further highlights the risks associated with use of this drug, which has been found to cause potentially fatal agranulocytosis (marked decrease in the number of white blood cells) in one every 100 treated patients, and deep venous thrombosis in at least 1 in 2-6-000 patients (based on spontaneous reporting), the latter complication being fatal in over 40% of cases.


PSYCHOTROPIC DRUGS  USED FOR
 ADULTS AND THE ELDERLY


Prescribing trends in psychotropic medications: primary care, psychiatry, and other medical specialties.
Pincus HA, Tanielian TL, Marcus SC, Olfson M, Zarin DA, Thompson J, Magno Zito J.
JAMA 1998 Feb 18;279(7):526-31.

The results of this study show that in 1985, in the U.S., 32.73 million visits to office-based primary care physicians resulted in prescription of psychotropic drugs. In 1994, the number of such visits increased to 45.64 million. Psychiatrists and primary care physicians' visits for depression doubled from 1988 to 1994, and visits for stimulants more than quadrupled. In addition, of the visits for depression, those paid to psychiatrists in 1994 resulted in a higher rate of drug prescribing, compared to 1988.


Expenditures for psychotropic medications in the United States in 1985.
Zorc JJ. et al.
Am J Psychiatry 1991 May;148(5):644-7.

This study shows that, in 1985, the U.S. spent $1.45 billion in psychotropic drugs for outpatients. Sixty percent of this sum ($868 million) was spent for antianxiety and sedative-hypnotic medications, 18% for antipsychotics, and 17% for antidepressants.


The direct economic costs of insomnia in the United States for 1995.
Walsh JK, Engelhardt CL.
Sleep 1999 May 1;22 Suppl 2:S386-93.

The results of this study show that in 1995, the U.S. spent $13.9 billion for the treatment of insomnia.


Psychotropic prescribing for the elderly in office-based practice.
Aparasu RR, Mort JR, Sitzman S.
Clin Ther 1998 May-Jun;20(3):603-16.

The results of this study show that 17% of visits by the elderly to office-based physicians result in the prescription of at least one inappropriate psychotropic drug. According to the study, in 1995, approximately 12 million visits by the elderly to their doctors resulted in prescription of a psychotropic drugs, primarily antidepressants and antianxiety drugs. In over 2 million visits, patients received a minimum of one potentially inappropriate psychotropic medication. The high rates of inappropriate prescribing, coupled with the particular susceptibility of elderly patients to experiencing drug-related adverse effects, raises concerns on the quality of care offered by physicians in ambulatory settings.


Determinants of psychotropic drug usage in a general intensive care unit.
Stolker J. et al.
Gen Hosp Psychiatry 1998 Nov;20(6):371-6.

The results of this study show that 36% and 17.5% of patients admitted to a Dutch general intensive care unit receive benzodiazepines and antipsychotics, respectively.


Psychotropic drug use and polypharmacy in a general hospital.
Salzman C.
Gen Hosp Psychiatry, 3(1):1-9 1981 Mar.

The results of this study show that approximately 43% of patients admitted to a general
Boston teaching hospital received psychotropic drugs. Drugs were given mainly for sleep problems or to reduce anxiety. The authors found high rates of inappropriate prescribing of antipsychotic drugs, which were given to control symptoms such as nausea, pain, or agitation rather than psychosis, and of antidepressant drugs, which were given irrespective of signs of depression, or below therapeutic doses in patients with depression.


Psychotropic use among older residents of board and care facilities.
Spore D. et al.
J Am Geriatr Soc, 43(12):1403-9 1995 Dec.

The results of this study, conducted on 2054 elderly residents from 410 board and care facilities in 10 states, indicate that approximately 35% of them were receiving a minimum of one psychotropic drug. Simultaneous use of 2 or more psychotropic drugs occurred in 30% of psychotropic drug users.


Regulatory environment and psychotropic use in board-and-care facilities: results of a 10-state study.
Spore D. et al.
J Gerontol A Biol Sci Med Sci, 51(3):M131-41 1996 May.

The results of this study, conducted on a sample population of 2,949 residents from 493 board-and-care facilities in 10 states, show that 41% of them were primarily or routinely being prescribed a minimum of one psychotropic drug. Twenty-one percent of residents were on antipsychotic drugs. About half of the individuals currently on psychotropic drugs did not have any psychiatric diagnosis in the previous year.


Psychotropic drug intake in residents newly admitted to nursing homes.
Wancata J. et al.
Psychopharmacology (Berl) 1997 Nov;134(2):115-20.

The results of this study indicate that prescribing of psychotropic drugs to nursing home residents occurs irrespective of prior history of psychiatric conditions. The study, conducted on a cohort of 262 individuals admitted to nursing homes in Austria, show that the prevalence of use of psychotropic drugs rose from 45.5% in the 3 months before admission, to 72% in the 2 weeks after admission, to 79% during the first six months of stay.


Psychotropic drug use in Sydney nursing homes.
Snowdon J. et al.
Med J Aust, 163(2):70-2 1995 Jul 17.

The results of this study, conducted on all residents of 46 nursing homes in Sydney, show that 59% of them were regularly receiving psychotropic drugs, and 7% of them were receiving them on an "as required" basis. Benzodiazepines, antipsychotics, hypnotics, antidepressants and anxiolytics were taken regularly by 32.3%, 27.4%, 26.6%, 15.6% and 8.6% of individuals, respectively.


A follow-up survey of psychotropic drug use in Sydney nursing homes.
Snowdon J.
Med J Aust 1999 Apr 5;170(7):299-301.

The results of this study show that 48.5% of Sidney nursing home residents receive at least one psychotropic drug regularly, and another 4.5% "as required". Antipshychotic drugs were taken by 27.6% of residents. Anticonvulsants, who were not considered in this study as psychotropic drugs, were given to 13% of residents.


Use of psychotropic medications for persons with mental retardation who live in Oklahoma nursing homes.
Spreat S. et al.
Psychiatr Serv, 49(4):510-2 1998 Apr.

The results of this study, conducted on a cohort of 1,056 individuals with mental retardation living in Oklahoma nursing homes, show that 32% of them were taking antipsychotic medications, 16% were taking anxiolytic drugs, and 6% were taking antidepressants. Use of antipsychotics, a class of drugs associated with a high risk of severe complications, was not always justified by patients' clinical history. The high rates of prescribing of antipsychotic drugs make the authors question the appropriateness of placing individuals with mental retardation in nursing homes.


Use of psychotropic medication in Oklahoma: a statewide survey.
Spreat S. et al.
Am J Ment Retard, 102(1):80-5 1997 Jul.

The results of this study indicate that 22.5%, 9.3%, and 5.9% of mentally retarded individuals are prescribed antipsychotic drugs, anxiolytics and antidepressant medications, respectively. Rates of prescribing for mentally retarded individuals living in institutions or intermediate care facilities are significantly higher.


Frequency of and determinants for psychotropic drug use in an institution for the mentally retarded.
Linaker OM.
Br J Psychiatry 1990 Apr;156:525-30.

The results of this study, conducted on a cohort of 168 mentally retarded individuals institutionalized in Norway, show that 49% of them were receiving antipsychotic drugs. Only in a small percentage of cases the prescription of these drugs could be justified by a psychiatric diagnosis.


Prevalence and prediction of psychotropic drug use in California developmental centers.
Stone RK. et al.
Am J Ment Retard, 93(6):627-32 1989 May.

The results of this study show that, on average, 35.4% of developmentally disabled individuals institutionalized in California are treated with psychotropic drugs, with 26.8% of them receiving antipsychotic medications. Rates of prescription of psychotropic drugs varied greatly among institutions, ranging from 13.7% to 63.6% of the individuals.


Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home: a controlled, double-blind study.
Cohen-Mansfield J, et al.
Arch Intern Med 1999 Aug 9-23;159(15):1733-40.

This double-blind placebo controlled study evaluated the effect of discontinuation of treatment with haloperidol, thioridazine, and lorazepam, three psychotropic drugs commonly used to control patient behavior, in residents of a nursing home. The behavior of patients who were slowly switched to placebo did not differ from that of patients who continued taking the drugs, questioning the efficacy of these medications in managing patient agitation. The authors conclude that an attempt to discontinue the use of such drugs should be routinely performed in nursing home settings.


Long-stay patients with long-stay drugs. A case review; a cause for concern.
Fottrell E, et al.
Lancet 1976 Jan 10;1(7950):81-2.

The results of this study, conducted on a cohort of 200 long-term psychiatric patients, show that approximately half of them were being prescribed unnecessary or excessive medications.


Clonidine impairs sustained attention and memory in Alzheimer's disease.
Riekkinen Jr P, Laakso MP, Jakala P, Riekkinen P Jr.
Neuroscience 1999;92(3):975-82.

The results of this study indicate that clonidine at doses of 2 microg/kg significantly disrupts attention and short-term memory in approximately one-third of Alzheimer patients. The negative effects of clonidine on attention were observed only in tests that were demanding for the patients, while those requiring simpler processing remained unaffected.


Psychotropic drug use and cognitive decline among older men and women.
Dealberto MJ. et al.
Int J Geriatr Psychiatry, 12(5):567-74 1997 May.

The results of this study, conducted on a cohort of 1200 individuals without cognitive impairment at baseline, show that users of non-benzodiazepine psychotropic drugs have a 5-fold increased risk of cognitive decline compared to nonusers.


Benzodiazepine use and cognitive function among community-dwelling elderly.
Hanlon JT, et al.
Clin Pharmacol Ther 1998 Dec;64(6):684-92.

The results of this study, conducted on 2765 elderly individuals living in the community and followed up for 3 years, show that current users of benzodiazepines experience significant worsening of memory function, compared to non-users. The association between benzodiazepine use and memory decline is dose-dependent, and exists with both short- and long-acting drugs.


Cognitive impairment in long-term benzodiazepine users.
Golombok S, Moodley P, Lader M.
Psychol Med 1988 May;18(2):365-74.

The results of this study indicate that long-term use of benzodiazepines is associated with significant cognitive impairment, particularly for tasks involving sustained attention and visual-spatial ability.


Anterograde amnesia linked to benzodiazepines.
Mejo SL.
Nurse Pract 1992 Oct;17(10):44, 49-50.

This article highlights that use of benzodiazepines is associated with disruption of long-term memory, a symptom that is often unrecognized by patients who take the drugs. The author concludes that is important that patients be fully informed on the side effects of treatment, and that the minimum possible dose be prescribed for the shortest period of time, in order to reduce the occurrence of treatment-induced adverse events.


Benzodiazepine use as a cause of cognitive impairment in elderly hospital inpatients.
Foy A, O'Connell D, Henry D, Kelly J, Cocking S, Halliday J.
J Gerontol A Biol Sci Med Sci 1995 Mar;50(2):M99-106.

The results of this study show that use of benzodiazepines significantly increases the risk of cognitive impairment in elderly individuals. The study was conducted on 418 individuals aged 59-88, with normal cognitive function upon admission to the hospital. During hospitalization, 10.8% of patients developed cognitive impairment. Patients who reported use of benzodiazepines were 3.5 times more likely to develop cognitive impairment, compared to nonusers. Overall, benzodiazepine use accounted for 30% of all cases of cognitive disruption.


Fatal myocardial infarction and use of psychotropic drugs in young women.
Thorogood M. et al.
Lancet, 340(8827):1067-8 1992 Oct 31.

The results of this study show that current use of psychotropic drugs in women aged 16 to 39 is associated with a 17-fold higher incidence of fatal myocardial infarction, compared to nonuse.


Use of psychotropic drugs and risk of myocardial infarction: a case-control study in Finnish farmers.
Penttinen J. et al.
Int J Epidemiol, 25(4):760-2 1996 Aug.

The results of this study, conducted on a cohort of 3172 male farmers, show that users of psychotropic drugs have a 2.5-fold increased risk of myocardial infarction, compared to nonusers. The risk of heart attack increased by 5.4-folds in users of antidepressants.


Psychotropic medication use and risk of epithelial ovarian cancer.
Harlow BL; et al.
Cancer Epidemiol Biomarkers Prev, 7(8):697-702 1998 Aug.

The results of this study, conducted on cohort of 563 women with ovarian cancer and 523 controls, show that users of psychotropic drugs for 6 or more months had a 60% increased risk of invasive ovarian cancer, compared to nonusers. In women who first used psychotropic drugs before menopause for more than two years, the risk increased by almost three times.


PSYCHOTROPIC DRUGS IN PREGNANCY


Psychotropic drug use during pregnancy: weighing the risks.
Cohen LS. et al.
J Clin Psychiatry, 59 Suppl 2():18-28 1998.

This article discusses some of the risks associated with use of psychotropic drugs by pregnant women, which include malformations, neonatal toxicity, and neurological and behavioral impairment. Additionally, it emphasizes that since the safety and efficacy of these drugs in the expecting mother has never been tested, nor their use has been approved by the FDA, a careful evaluation of the risks and benefits of treatment should be conducted before psychotropic drugs are taken during pregnancy.


Psychotropic drug use in pregnancy and perinatal death.
Laegreid L. et al.
Acta Obstet Gynecol Scand, 71(6):451-7 1992 Aug.

This study analyzed psychotropic drug use in a sample population of 73 mothers of dead infants and in a control cohort of mothers of surviving infants, and found that psychotropic drug use was significantly associated with perinatal death.


Use of psychotropic drugs and pregnancy outcome.
Larivaara P; et al.
J Clin Epidemiol, 49(11):1309-13 1996 Nov.

The results of this study, conducted on a cohort of 7933 pregnant women and their 8030 babies, show that use of psychotropic drugs during pregnancy is significantly associated with an increased need for hospital observation. In particular, 80.8%, and 38.3% of regular and occasional psychotropic drug users required hospital observation, compared to 27.4% of nonusers. In addition, bleeding was significantly more frequent in users vs. nonusers (23% vs. 13%), and infant mean birth weight was significantly lower among regular users.


Neurodevelopment in late infancy after prenatal exposure to benzodiazepines--a prospective study.
Laegreid L. et al.
Neuropediatrics, 23(2):60-7 1992 Apr.

This study evaluated neurodevelopment and growth in 17 children of mothers who used therapeutic doses of benzodiazepines (BZD) throughout pregnancy. Follow up was performed at 6, 10, and 18 months of age. Children exposed to BZD had slightly reduced head circumference at birth and throughout follow up, compared to children of women who were not exposed to BZD. Craniofacial abnormalities were present in 5 infants. Gross motor development was impaired at 6 and 10 months while fine motor development was impaired throughout follow up. Deviating muscle tone and movements were found more frequently in children exposed to BZD compared to controls. These data indicate that exposure to therapeutic levels of BZD during pregnancy is associated with a significantly higher risk of abnormal development in the offspring.


Mental development in late infancy after prenatal exposure to benzodiazepines--a prospective study.
Viggedal G, Hagberg BS, Laegreid L, Aronsson M.
J Child Psychol Psychiatry 1993 Mar;34(3):295-305.

The results of this study show that continuous use of benzodiazepines during pregnancy is associated with significant impairment of mental development in the offspring.


Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies.
Dolovich LR, et al.
BMJ 1998;317:839-843 ( 26 September ).

This article presents the results of a meta-analysis of 23 selected studies investigating whether use of benzodiazepine during the first trimester of pregnancy increases the risk of major malformations or oral cleft in the offspring. While cohort studies did not detect an increased incidence of major malformations or oral cleft, analysis of case-control studies revealed a 3-fold increase in incidence of major malformations and an 80% increase in incidence of oral cleft alone in the offspring of benzodiazepine users, compared to controls.


DRUGS, FALLS AND HIP FRACTURES


Injurious falls in nonambulatory nursing home residents: a comparative study of circumstances, incidence, and risk factors.
Thapa PB. et al.
J Am Geriatr Soc 1996 Mar;44(3):273-8.

The results of this study show that ambulatory nursing home residents who take psychotropic drugs have a 2.5-fold increased risk of falls resulting in injuries, compared to those not on these drugs.


Psychotropic drugs and risk of recurrent falls in ambulatory nursing home residents.
Thapa PB. et al.
Am J Epidemiol 1995 Jul 15;142(2):202-11.

The results of this study show that 36% of all recurrent falls in ambulatory nursing home residents can be attributed to psychotropic drug use.


Relationship between the administration of selected medications and falls in hospitalized elderly patients.
Gales BJ. et al.
Ann Pharmacother, 29(4):354-8 1995 Apr.

The results of this study, conducted on a sample group of 100 patients aged 70 and older who fell and 100 control subjects of the same age, show that benzodiazepine use in fallers was 2.7 times more frequent that in non users. Sixty-five percent of patients who fell while taking long-acting benzodiazepines, were taking higher than recommended doses of the drug. Congestive heart failure, treatment with digoxin and use of 3 or more psychotropic drugs were all factors positively associated with an increased risk of falls.


Falls, injuries due to falls, and the risk of admission to a nursing home.
Tinetti ME, et al.
N Engl J Med 1997 Oct 30;337(18):1279-84.

The results of this study, conducted on a sample group of 1103 elderly individuals living in the community, show that those who fall are at significantly increased risk of being admitted to a nursing home, compared to the remaining population. In particular, the risk of being admitted to a nursing home increases by 3 times in those with one noninjurious fall, by 5.5-times in those with multiple noninjurious falls, and by more than 10 times in those with one or more injurious fall. These data suggest that interventions aiming at reducing the incidence of falls can substantially reduce the number of admission to nursing homes.


Potential adverse outcomes of psychotropic and narcotic drug use in Canadian seniors.
Ebly EM. et al.
J Clin Epidemiol 1997 Jul;50(7):857-63.

The results of this study, conducted on a large population of elderly individuals with intact cognition, show that the incidence of falls is 3 times greater in users of two or more psychotropic drugs, compared to nonuser (42.6% versus 13.9%). These data indicate that psychotropic drug-related adverse effects may significantly increase the risk of falls in elderly individuals.


Effects of central nervous system polypharmacy on falls liability in community-dwelling elderly.
Weiner DK. et al.
Gerontology 1998;44(4):217-21.

The results of this study, conducted on a cohort of 305 community-dwelling elderly individuals, show that use of one psychotropic drug is associated with a 54% increased risk of falls, while use of two or more psychotropic drugs is associated with a 137% increased risk of falls. The authors conclude that the dose-response effect is indicative of a relation of causality between use of psychotropic drugs and falls.


Antidepressants and the risk of falls among nursing home residents.
Thapa PB. et al.
N Engl J Med 1998 Sep 24;339(13):875-82.

The results of this study, conducted on a sample population of 2428 nursing home residents, show that use of the antidepressants tricyclics, serotonin-reuptake-inhibitors and trazodone, is associated with a 2.0-, 1.8- and 1.2-fold increased risk of falls, respectively.


Risk factors for falls as a cause of hip fracture in women. The Northeast Hip Fracture Study Group.
Grisso JA. et al.
N Engl J Med 1991 May 9;324(19):1326-31.

The results of this study show that use of long-acting barbiturates in the elderly is associated with a 5.2-fold increased risk of hip fractures.


Opioid analgesics and the risk of hip fracture in the elderly: codeine and propoxyphene.
Shorr RI. et al.
J Gerontol 1992 Jul;47(4):M111-5.

The results of this study, conducted on a cohort of 4,500 elderly individuals and 24,041 matched controls, show that users of the commonly prescribed anti-pain medications codeine or propoxyphene have a 60% increased risk of hip fractures, compared to nonusers. The risk of hip fractures increases by 2.2-times in new users of the drugs, and by 2.6 times in those who take them in combination with a psychotropic drug. These findings are important, especially in consideration of the widespread prescribing of anti-pain medications to elderly individuals.


Cognitive impairment, drug use, and the risk of hip fracture in persons over 75 years old: a community-based prospective study.
Guo Z. et al.
Am J Epidemiol 1998 Nov 1;148(9):887-92.

The results of this study, conducted on a sample group of 1,608 individuals aged 75 and older, show that those using the opioid analgesic propoxyphene have a two-fold increased risk of hip fractures, compared to nonusers. In addition, use of potassium supplements was associated with a 45% reduction in hip fracture risk.


Cyclic antidepressants and the risk of hip fracture.
Ray WA, et al.
Arch Intern Med 1991 Apr;151(4):754-6.

The results of this study show that elderly individuals using tricyclic antidepressants have a 60% increased risk of hip fractures, compared to nonusers.


Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of hip fractures in elderly people.
Liu B, et al.
Lancet 1998 May 2;351(9112):1303-7.

The results of this study, performed on a sample group of 8,239 elderly individuals with hip fracture and five controls matched to each subject, show that use of the antidepressants selective serotonin-reuptake inhibitors, secondary-amine tricyclics and tertiary-amine tricyclics, was associated with a 2.4-, 2.2-, and 1.5-fold increased risk of hip fractures, respectively, compared to nonuse. New use of each class of drugs resulted in a further increase in the risk of hip fractures.


Benzodiazepines of long and short elimination half-life and the risk of hip fracture.
Ray WA, et al.
JAMA 1989 Dec 15;262(23):3303-7.

The results of this study, conducted on a cohort of 4501 elderly individuals with hip fracture and 24,041 controls, show that use of long-acting benzodiazepines is associated with a 70% increased risk of hip fractures.


Effect of a single dose of diazepam on balance measures in older people.
Cutson TM, Gray SL, Hughes MA, Carson SW, Hanlon JT.
J Am Geriatr Soc 1997 Apr;45(4):435-40.

The results of this study show that diazepam adversely affects balance control in elderly individuals. The researchers evaluated the effects of a single dose of diazepam on balance in 12 healthy individuals aged 65 and older. Administration of the drug was associated with prolongation of the latency time of the muscle of the lower leg in response to a sudden perturbation, and with impaired performance at neuropsychological tests of attention. These findings seem to confirm the epidemiological finding of an increased risk of falls associated with use of benzodiazepines.


Psychotropic drug use and the risk of hip fracture.
Ray WA; Griffin MR; Schaffner W; Baugh DK; Melton LJ 3d.
N Engl J Med, 316(7):363-9 1987 Feb 12.

The results of this study, conducted on a cohort of 1021 elderly patients with hip fracture and 5606 controls, show that use of long-acting hypnotics-anxiolytics, tricyclic antidepressants, and antipsychotics drugs is associated with an 80%, 90%, and 2-fold increased risk of hip fractures, respectively, compared to nonuse. The risk of fractures increases with increasing doses of these drugs, thus suggesting a relation of causality between drug use and injurious falls.


Diuretic drug use and the risk for hip fracture.
Heidrich FE, et al.
Ann Intern Med 1991 Jul 1;115(1):1-6.

The results of this study, conducted on a cohort of 462 elderly patients hospitalized for hip fractures and 462 matched controls, show that current use of thiazide diuretics is associated with a 60% increased risk of hip fractures, compared to nonuse. Use of the diuretic furosemide was associated with an almost 4-fold increased risk of fracture.


Psychotropics, thiazide diuretics and hip fractures in the elderly.
Cumming RG. et al.
Med J Aust 1993 Mar 15;158(6):414-7.

The results of this study, conducted on a sample group of 209 individuals with hip fracture and 207 controls, show that use of the benzodiazepine temazepan is associated with a 3.5-fold increased risk of hip fractures, compared to nonuse. Intake of thiazide diuretics in this study was not associated with a higher risk of fractures.


Rheumatoid arthritis, corticosteroid therapy and hip fracture.
Cooper C, et al.
Ann Rheum Dis 1995 Jan;54(1):49-52.

The results of this study show that patients with rheumatoid arthritis and those taking corticosteroids have a 2.0- and 2.7-fold increased risk of hip fractures, respectively, compared to patients without this condition and not using these drugs. After adjusting for functional impairment, the risk decreased in patients with RA, but remained high in those taking corticosteroids.


Hip fractures and fluoridation in Utah's elderly population.
Danielson C, et al.
JAMA 1992 Aug 12;268(6):746-8.

The results of this large ecological study, conducted on all elderly individuals from three communities in Utah who presented with hip fractures over a 7-year period, show that men and women living in fluoridated areas had a 41% and 27% increased risk of hip fractures, respectively, compared to those living in areas without fluoridated water.


Quality of life related to fear of falling and hip fracture in older women: a time trade off study.
Salkeld, G. et al.
BMJ 2000;320:341-346 ( 5 February ).

The results of this study, conducted on a sample group of 194 women aged 75 and older, show that 80% of them would rather die than lose their independence and be admitted to a nursing home after a bad hip fracture.


PSYCHOTROPIC DRUGS AND MOTOR VEHICLE ACCIDENTS


Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers.
Ray WA. et al.
Am J Epidemiol, 136(7):873-83 1992 Oct 1.

The results of this study, conducted on a cohort of 16,262 individuals aged 65 and older, show that users of benzodiazepines have a 50% increased risk of motor vehicle crashes, compared to nonusers. Use of tricyclic antidepressants was associated with an over twofold increased risk of crashes, and the risk increased with increasing drug dosage, being 5.5-times higher in users of 125 mg or more of amitriptyline, compared to nousers.


Association of road-traffic accidents with benzodiazepine use.
Barbone F, et al.
Lancet 1998 Oct 24;352(9137):1331-6.

The results of this study show that use of long half-life benzodiazepines (used to treat anxiety) and of short half-life hypnotics (zopiclone) is associated with an increased risk of motor vehicle crash in individuals aged 18 and older. The risk increases with increasing doses of benzodiazepine.


Benzodiazepine use among the elderly in the community.
Kirby M, et al.
Int J Geriatr Psychiatry 1999 Apr;14(4):280-4.

The results of this study show that 17% of community-dwelling elderly individuals in Ireland take benzodiazepines, which are, in over 50% of cases, of the long-acting form. The high rate of prescription of long-acting benzodiazepines causes concern, since these drugs have been associated with an increased risk of hip fractures and motor vehicle crashes in the elderly.


ANTIPSYCHOTICS


Growth patterns in the developing brain detected by using continuum mechanical tensor maps.
Thompson PM, Giedd JN, Woods RP, MacDonald D, Evans AC, Toga AW.
Nature 2000 Mar 9;404(6774):190-3.

The results of this study show that brain cells continue to grow and organize at least into puberty. The researchers scanned the brain of children at intervals of up to 4 years, from the age of 3 to 15 years. They observed waves of growth at the fiber system that relays information between the right and left side of the brain, throughout the follow-up period, with growth occurring predominantly in the frontal regions, associated with the planning of new actions, earlier in age, and subsequently in the mid- and posterior regions of the brain, where associative thinking and language are regulated. These data indicate that brain development can be affected throughout puberty, contradicting previous theories which viewed the brain as essentially organized by the time a child reach the age of 6. The effects of psychotropic drugs on the evolving brain must be carefully evaluated, since these drugs have the potential of interfering with its development.


A comparison of prazepam, diazepam, lorazepam and placebo in anxious outpatients in non-psychiatric private practices.
Zung WW; et al.
J Clin Psychiatry, 42(7):280-4 1981 Jul.

The results of this double-blind, randomized, placebo controlled study, show that the anxiolytics prazepam, diazepam, lorazepam, or placebo were all effective in relieving anxiety and depression in patients predominantly depressed with anxiety, while only placebo and prazepam reduced both symptoms in patients predominantly anxious with depression. These data suggest that anxyolytics are no better than placebo in the management of patients with anxiety and depression.


Benzodiazepines for depression? A review of the literature.
Birkenh¨ager TK; et al.
Int Clin Psychopharmacol, 10(3):181-95 1995 Sep

This study shows that combination therapy with benzodiazepines and tricyclic antidepressants (TCA) for treatment of depression is not superior, beyond the first few weeks of treatment, to monotherapy with TCAs.


Worsening of symptoms of multiple sclerosis associated with carbamazepine. Letter.
Ramsaransing G, Zwanikken C, De Keyser J.
BMJ 2000;320:1113 ( 22 April ).

This article reports on the worsening of symptoms of multiple sclerosis associated with use of carbamazepine, a tricyclic drug used to treat some forms of pain, convulsions, epilepsy, and manic episodes. The case of five patients with severe aggravation of disease following initiation of treatment and with symptoms resolution after carbamazepine discontinuation is presented. In one case, the onset of new symptoms (loss of the ability to walk) was interpreted as progression of disease and the patient, rather than having carbamazepine treatment interrupted, was aggressively treated with intravenous corticosteroids without improvement. Only after being discharged from the hospital, carbamazepine was stopped and the patient resumed her ability of walking.


Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks.
Philipp M. et al.
BMJ 1999;319:1534-1539 ( 11 Dec ).

This double blind, placebo controlled study shows that the herbal supplement hypericum extract (St. John's Wort) (1050 mg per day) is as effective as the antidepressant imipramine (100 mg per day) in alleviating symptoms in moderately depressed patients. Furthermore while patients in the hypericum arm reported improvement in the physical scale of a quality of life questionnaire, patients in the imipramine arm did not. Patients taking hypericum experienced the same rate of adverse reactions of patients taking placebo, and less than half the rate of those taking imipramine.


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