The association between substance abuse and antidepressant-induced mania in bipolar disorder: a preliminary study.

Goldberg JF, Whiteside JE.

Department of Psychiatry, Weill Medical College of Cornell University, New York, NY, USA. JFGoldbe mail.med.cornell.edu

BACKGROUND: Estimates of the prevalence and features of antidepressant-induced mania vary widely, with few data available on its potential risk factors. METHOD: Fifty-three DSM-IV bipolar patients were interviewed to retrospectively identify lifetime affective episodes, pharmacotherapy trials, and clinical outcomes, with corroboration from treating clinicians and reviews of medical, psychiatric, and pharmacy records. Particular attention was given to the possible relationship between antidepressant-induced mania and the presence of psychoactive substance abuse or dependence. RESULTS: Antidepressant-induced mania or hypomania was evident in 39.6% (21/53) of the study group. Patients who developed manic features soon after starting an antidepressant had more antidepressant trials per year than those who did not (p < .05). A history of substance abuse and/or dependence was associated with substantially increased risk for antidepressant-induced mania (odds ratio = 6.99, 95% CI = 1.57 to 32.28, p = .007). Concomitant mood stabilizers were not uniformly associated with protection against inductions of mania during antidepressant trials. CONCLUSION: Multiple antidepressant exposures among bipolar patients with histories of substance abuse and/or dependence may be associated with an elevated risk for antidepressant-induced mania.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12363119&dopt=Abstract antidepressant




Are placebo controls necessary to test new antidepressants and anxiolytics?

Khan A, Khan S, Brown WA.

Northwest Clinical Research Center, Bellevue, WA 98004, USA. akhan nwcrc.net

One measure of a treatment's effectiveness is the regularity with which it proves superior to placebo. That measure also tells us about the consequences of using a treatment as a standard against which to test a new agent. To assess the frequency with which approved and presumably effective antidepressants and anxiolytics show statistical superiority over placebo, we reviewed placebo-controlled clinical trials of antidepressants and anxiolytics in a singularly large database free of publication bias. We evaluated clinical-trial data from the nine antidepressants approved by the FDA between 1985 and 2000. These trials comprised 10030 depressed patients who participated in 52 antidepressant clinical trials evaluating 93 treatment arms of a new or established antidepressant. Similarly, we examined clinical trials data from the 13 anxiolytics approved by the FDA between 1985 and 2000. These trials comprised 8,340 anxious patients, 40 anxiolytic clinical trials and 75 treatment arms of a new or established anxiolytic. Fewer than half (48%, 45/93) of the antidepressant treatment arms showed superiority to placebo. Among anxiolytics, 48% (36/75) of anxiolytic treatment arms showed superiority over placebo. These data suggest that conventional psychopharmacologic treatments for depression and anxiety are superior to placebo less than half the time and call into serious question the widely propagated notion that placebo controls can be dispensed with in clinical trials of these agents. Exclusion of placebo controls in favour of non-inferiority trials would result in a high likelihood that ineffective antidepressants and anxiolytics would be foisted on the public and, less dangerous but also problematic, that potentially effective agents would be missed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12366872&dopt=Abstract antidepressant




[Increasing significance of antidepressants in deliberate self-poisoning]

[Article in German]

Von Mach MA, Weilemann LS.

Klinische Toxikologie und Beratungsstelle bei Vergiftungen, II. Medizinische Klinik und Poliklinik, Klinikum der Johannes Gutenberg-Universitat Mainz, Germany. marcm giftinfo.uni-mainz.de

BACKGROUND AND OBJECTIVE: Antidepressant drugs are frequently used in deliberate self-poisoning resulting in a major risk for the patients due to their cardiac and central-nervous toxicity. In the present study the cases of intoxications consulting our Poison Center should be analysed illustrating recent results and trends about self-poisoning with antidepressants. PATIENTS AND METHODS: During the study period from 1995 to 2001 35 394 inquiries concerning deliberate self-poisoning were registered in our Poison Center. The substance used, age and gender of the patient as well as the degree of the observed symptoms were documented. Thereby, antidepressant drugs were grouped in tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI) and other antidepressants. RESULTS: The use of antidepressants in deliberate self-poisoning continuously increased during the study period from 17.3 % to 22.9 % with SSRI and other antidepressants being observed more frequently as compared to TCA. Antidepressant drugs were mainly used from female patients and in the age group between 35 and 54 years. Antidepressant drugs caused severe intoxications and deaths more frequently as the remainder substances with TCA showing higher rates of complications as compared to SSRI and other antidepressants. CONCLUSIONS: In recent years, an increasing importance of antidepressant drugs in deliberate self-poisoning was determined particularly concerning female and middle-aged patients. Due to the changing prescribing patterns larger numbers of intoxications with SSRI and other antidepressants were observed representing an advantage with respect to the reduced rate of complications known for these substances as compared to TCA. Nevertheless, the averagely more severe symptoms present in the three groups of antidepressants in comparison to the remainder drug overdoses demonstrated the need for hospitalization and monitoring of intoxications with antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12373636&dopt=Abstract antidepressant




Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme.

Zhang HT, Huang Y, Jin SL, Frith SA, Suvarna N, Conti M, O'Donnell JM.

Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA. hzng utmem.edu

Pharmacological inhibition of type 4 cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE4) produces antidepressant-like effects in animals; however, it is not known which of the four PDE4 subtypes mediates these actions. In the present study, immunoblot analysis showed loss of phosphodiesterase 4D (PDE4D) expression in the cerebral cortex and hippocampus of PDE4D knockout (PDE4D-/-) mice, but unchanged PDE4A and PDE4B expression, relative to the wild type (PDE4D+/+) and heterozygous knockout (PDE4D+/-) mice. This reduced expression was accompanied by a reduction in PDE4 activity, while non-PDE4 activity was unchanged. PDE4D-/- mice exhibited decreased immobility in tail-suspension and forced-swim tests, which is indicative of an antidepressant-like effect on behavior. Desipramine and fluoxetine produced similar antidepressant-like effects in all three genotypes, even though their behavioral baselines differed markedly. By contrast, the PDE4 inhibitor rolipram only produced antidepressant-like effects in PDE4D+/+ mice. Consistent with this, rolipram potentiated isoproterenol-induced cyclic AMP formation only in the PDE4D+/+ mice. These results suggest that PDE4D is an essential mediator of the antidepressant-like effects of rolipram, and that PDE4D-regulated cyclic adenosine monophosphate signaling may play a role in the pathophysiology and pharmacotherapy of depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12377395&dopt=Abstract antidepressant




[Antidepressants consumption in the global population in France]

[Article in French]

Olie JP, Elomari F, Spadone C, Lepine JP.

Service Hospitalo-Universitaire, CH Sainte-Anne, 1, rue Cabanis, 75014 Paris-Universite Paris V, France.

The consumption of antidepressant seems to be in France higher than in comparable countries, as well as the overall consumption of healthcare and medications. In Western countries, in recent years, the use of antidepressants has regularly increased, mainly due to the use of serotoninergic antidepressants. In France, in a week, the prevalence of antidepressant use in the overall population increased from 1.7% in 1992 to 3% in 1995. This survey addressed the overall population in the form of a representative sample focusing on subjects who indicated, at the time they were consulted, that they were taking an antidepressant. The study aimed to determine the circumstances of prescription: prescriber file, reason for prescription, type of medication prescribed, match between the prescription and the product indications stated in the marketing authorization, prescription duration and reason for discontinuing treatment. Methodology - The first stage consisted in forwarding a letter to a panel of 44 000 subjects aged 15 years or more and representative of the French population. The aim was to achieve a cross-sectional description of the population taking antidepressants. The response rate was 82% (36 036 subjects). The subjects who stated that they were taking an antidepressant were re-contacted by telephone by an interviewer trained in the use of the Composite International Diagnostic Interview - lifetime (CIDI), exploring depression and anxiety diseases with a view to potential diagnosis as per DSM criteria. Longitudinal follow-up over 8 months from the initial screening was evaluated using a monthly questionnaire on the time course of antidepressant consumption. Results - Out of 20 000 households, comprising 44 000 people aged over 15 years, 1 333 people were taking an antidepressant or had taken one in the previous 4 weeks. The sex ratio of the antidepressant consumers was 3 women to 1 man, amplifying the known sex ratio with respect to depressive disorders. The mean age of the subjects taking an antidepressant at time t was 51 years. Lifestyle and socioprofessional category did not seem to influence antidepressant consumption. Somatic comorbidity was present in 60% of antidepressant consumers. Among the consumers of antidepressants at time t, 45% were taking a selective serotonin reuptake inhibitor (SSRI). The two products most widely prescribed in that class were fluoxetine (30% of the subjects taking an antidepressant at time t) and paroxetine (10% of the subjects taking an antidepressant at time t). The other SSRIs accounted for the remaining 5%. Thirty-nine percent of the consumers were taking a tricyclic antidepressant: clomipramine in 16% of cases, amitriptyline in 14%, and other tricyclic antidepressants in 9%. Lastly, 20% of the consumers were taking an antidepressant that was neither an SSRI nor a tricyclic antidepressant. Only 4% of the patients were concomitantly taking 2 antidepressants: single-agent therapy is in line with the recommendations of the various expert groups. In the survey, 9 antidepressant prescriptions out of 10 were written by an open-care practitioner, and 1 out of 10 by a hospital physician. For 60% of the subjects, the antidepressant treatment was prescribed by a general practitioner. General practitioners prescribe less tricyclic antidepressants and more SSRIs than specialists. The main reason for prescription reported by the patient was depression (57% of cases); followed by a state of anxiety or stress (15% of cases). In 10% of cases, the consumer stated that the reason for treatment was not psychological. Sixty-two percent of subjects presented with, or had presented with, a mood disorder as per M-CIDI (major depression, mood disorder, or a combination of the two) and 14% an isolated anxiety disorder. Twenty-five percent of the subjects on antidepressants did not fulfill all the M-CIDI criteria for any diagnosis. Among the people receiving antidepressants, 54% had a CIDI diagnosis in strict compliance with the marketing authorization indications for the product considered. One quarter (25%) presented with a diagnosis of a characterized psychiatric disease, outside of the marketing authorization indications for the product taken. This finding reflects misuse or use on the basis of published data not incorporated in the marketing authorization. The dosages were in line with those stated in the marketing authorization for the disease considered in almost 99% of cases for the subjects on paroxetine and fluoxetine, but for only 22% of cases for the subjects on tricyclic antidepressants. Tricyclic antidepressants would therefore appear to be frequently inappropriately in terms of proportions that would be ineffective: half of the subjects on clomipramine were taking a dose less than or equal to one third of the minimum recommended dose. Conclusion - This survey shows that the point-prevalence of antidepressants in the global population in France is about 3.5%. Women consume more antidepressants than men. SSRIs are the most widely prescribed antidepressants. The survey findings point out the discrepancies between official indications, such as the ones issued by the regulatory authorities, and the physicians' prescribing practices.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12386542&dopt=Abstract antidepressant




A survey of prescribing preferences in the treatment of refractory depression: recent trends.

Kornbluh R, Papakostas GI, Petersen T, Neault NB, Nierenberg AA, Rosenbaum JF, Fava M.

McLean Hospital, Belmont, MA, USA.

The objective of this study was to gather data from a large group of clinicians on antidepressant prescribing practices in the treatment of refractory depression. Eight hundred and thirty-five clinicians about to attend the annual Massachusetts General Hospital psychopharmacology review course were asked to respond to a brief questionnaire regarding a hypothetical clinical case vignette. The case was of a patient who suffered from a new onset, unipolar, nonpsychotic, severe major depressive episode. Three hundred and four (36%) clinicians agreed to participate and filled out our questionnaire. Of the respondents, 260 (85.5%) indicated their preference for an initial treatment that combined medication and psychotherapy, as opposed to either modality alone. Furthermore, given this patient's nonresponse to two adequate selective serotonin reuptake inhibitor (SSRI) trials and one atypical antidepressant trial over an 8-month period, 39.8% of respondents indicated venlafaxine monotherapy as their next choice, whereas combining antidepressants (20.1%) and augmentation (18.4%) were the second and third most preferred treatment choices at this time point. Further on in the course of treatment, with the patient not having responded to any interventions during a 16-month period, 80.9% of survey respondents indicated electroconvulsant therapy (ECT) as their next preference. Among 304 clinicians surveyed, a combination of therapy and medication is the most preferred choice for treating severely depressed outpatients with new onset depression. Switching to venlafaxine, using two antidepressants together, and augmentation of an antidepressant regimen with a second agent accounted for 78.3% of respondents' preferences when faced with treating a depressed patient who had not responded to two adequate SSRI trials and one adequate atypical antidepressant trial. Of the respondents, 80.9% indicated ECT as a treatment preference after 16 months of multiple failed medication trials and nonresponse to psychotherapy. Further research is necessary to elucidate the factors that influence clinicians' reasoning for selecting one strategy over another.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12397884&dopt=Abstract antidepressant




Milnacipran: an antidepressant with dual selectivity of action on noradrenaline and serotonin uptake.

Delini-Stula A.

CNS Medical Research Counselling, Stoberstrasse 36, CH 4055 Basle, Switzerland.

Milnacipran is a new antidepressant which possesses potent and doubly selective action in that it inhibits both the re-uptake of serotonin and noradrenaline without any effect on other neurotransmitter systems. The almost equipotent inhibition of serotonin and noradrenaline by milnacipran is functionally reflected in the several-fold and long-lasting increase of the levels of these monoamines in the brain and in antidepressant-like effects in animals. In man, milnacipran distinguishes itself from many other antidepressants by its simple pharmacokinetics. It shows linear dose-concentration relationship over a dose range of 25-200 mg/day. It is rapidly and extensively absorbed and almost completely eliminated after 12 h (t1/2 approx. 8 h). Steady-state plasma levels are reached within 32-48 h after twice daily oral administration. Milnacipran is highly bioavailable (>85 per cent) and its metabolism does not involve the cytochrome P450 enzyme system. In clinical studies, milnacipran showed antidepressant efficacy similar to that of TCAs and SSRIs and superior to that of placebo. At the optimum dose of 100 mg/day, after 4-8 weeks of treatment, 60-64 per cent of in- or out-patients with major depression improve (>/=50 per cent reduction of HAMD and MADRS score) and about 32-39 per cent of them achieve full remission (HAMD score</=7). Milnacipran has proved to be a very safe drug with a benign adverse event profile clearly superior to that of TCAs and, to a certain extent, that of SSRIs. Only about 10 per cent of patients experience side-effects and only dysuria occurred more frequently (2 per cent) with milnacipran than with TCAs or SSRIs. Milnacipran appears therefore to be an antidepressant with a very favourable benefit/risk ratio. Copyright 2000 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12404320&dopt=Abstract antidepressant




Use of antidepressant medications in the general practice setting. A critical review.

Hegarty K, Ames D, Anderson J, Johnson C, McKinnon R, Moulds R.

Department of General Practice, University of Melbourne, Victoria.

BACKGROUND: Antidepressants are commonly prescribed in general practice for depression, but also for a wide range of other psychiatric conditions and physical problems. OBJECTIVE: This review, although concentrating on the use of antidepressants in depression, also reviews their use in other conditions commonly seen in general practice. DISCUSSION: For most major depression, all antidepressant drugs have equal efficacy. The choice of antidepressant drug needs to be tailored to the particular patient's medical condition and personal preferences. It is likely that adverse effects are the major determinant in the choice of antidepressant for a particular patient. However, in treating conditions other than depression, the efficacy of the antidepressant drug can be the primary issue of drug choice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12735262&dopt=Abstract antidepressant