Neuropsychiatric adverse effects of interferon-alpha: recognition and management.

Raison CL, Demetrashvili M, Capuron L, Miller AH.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA. craison emory.edu

Recombinant preparations of the cytokine interferon (IFN)-alpha are increasingly used to treat a number of medical conditions, including chronic viral hepatitis and several malignancies. Although frequently effective, IFN alpha induces a variety of neuropsychiatric adverse effects, including an acute confusional state that develops rapidly after initiation of high-dose IFN alpha, a depressive syndrome that develops more slowly over weeks to months of treatment, and manic conditions most often characterised by extreme irritability and agitation, but also occasionally by euphoria. Acute IFN alpha-induced confusional states are typically characterised by disorientation, lethargy, somnolence, psychomotor retardation, difficulties with speaking and writing, parkinsonism and psychotic symptoms. Strategies for managing delirium should be employed, including treatment of contributing medical conditions, use of either typical or atypical antipsychotic agents and avoidance of medications likely to worsen mental status. Significant depressive symptoms occur in 21-58% of patients receiving IFN alpha, with symptoms typically manifesting over the first several months of treatment. The most replicated risk factor for developing depression is the presence of mood and anxiety symptoms prior to treatment. Other potential, but less frequently replicated, risk factors include a past history of major depression, being female and increasing IFN alpha dosage and treatment duration. The available data support two approaches to the pharmacological management of IFN alpha-induced depression: antidepressant pretreatment or symptomatic treatment once IFN alpha has been initiated. Pretreatment might be best reserved for patients already receiving antidepressants or for patients who endorse depression or anxiety symptoms of mild or greater severity prior to therapy. Several recent studies demonstrate that antidepressants effectively treat IFN alpha-induced depression once it has developed, allowing the vast majority of subjects to complete treatment successfully. Recent data suggest that IFN alpha-induced depression may be composed of two overlapping syndromes: a depression-specific syndrome characterised by mood, anxiety and cognitive complaints, and a neurovegetative syndrome characterised by fatigue, anorexia, pain and psychomotor slowing. Depression-specific symptoms are highly responsive to serotonergic antidepressants, whereas neurovegetative symptoms are significantly less responsive to these agents. These symptoms may be more effectively treated by agents that modulate catecholaminergic functioning, such as combined serotonin-noradrenaline (norepinephrine) antidepressants, bupropion, psychostimulants or modafinil. Additional factors to consider in selecting an antidepressant include potential drug-drug interactions and adverse effect profile. Finally, IFN alpha appears capable of inducing manic symptoms. Mania, especially when severe, is a clinical emergency. When this occurs, IFN alpha and antidepressants should be stopped, an emergency psychiatric consultation should be obtained, and treatment with a mood stabilizer should be initiated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15697325&dopt=Abstract antidepressant




The relationship between antidepressant medication use and rate of suicide.

Gibbons RD, Hur K, Bhaumik DK, Mann JJ.

Center for Health Statistics, University of Illinois at Chicago, USA.

BACKGROUND: Approximately 30 000 people die annually by suicide in the United States. Although 60% of suicides occur during a mood disorder, mostly untreated, little is known about the relationship between antidepressant medication use and the rate of suicide in the United States. OBJECTIVE: To examine the association between antidepressant medication prescription and suicide rate by analyzing associations at the county level across the United States. DESIGN: Analysis of National Vital Statistics from the Centers for Disease Control and Prevention. SETTING: All US counties. PARTICIPANTS: All US individuals who committed suicide between 1996 and 1998. MAIN OUTCOME MEASURES: National county-level suicide rate data are broken down by age, sex, income, and race for the period of 1996 to 1998. National county-level antidepressant prescription data are expressed as number of pills prescribed. The primary outcome measure is the suicide rate in each county expressed as the number of suicides for a given population size. RESULTS: The overall relationship between antidepressant medication prescription and suicide rate was not significant. Within individual classes of antidepressants, prescriptions for selective serotonin reuptake inhibitors (SSRIs) and other new-generation non-SSRI antidepressants (eg, nefazodone hydrochloride, mirtazapine, bupropion hydrochloride, and venlafaxine hydrochloride) are associated with lower suicide rates (both within and between counties). A positive association between tricyclic antidepressant (TCA) prescription and suicide rate was observed. Results are adjusted for age, sex, race, income, and county-to-county variability in suicide rates. Higher suicide rates in rural areas are associated with fewer antidepressant prescriptions, lower income, and relatively more prescriptions for TCAs. CONCLUSIONS: The aggregate nature of these observational data preclude a direct causal interpretation of the results. A high number of TCA prescriptions may be a marker for those counties with more limited access to quality mental health care and inadequate treatment and detection of depression, which in turn lead to increased suicide rates. By contrast, increases in prescriptions for SSRIs and other new-generation non-SSRIs are associated with lower suicide rates both between and within counties over time and may reflect antidepressant efficacy, compliance, a better quality of mental health care, and low toxicity in the event of a suicide attempt by overdose.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15699293&dopt=Abstract antidepressant




Fatal toxicity of antidepressants in England and Wales, 1993-2002.

Morgan O, Griffiths C, Baker A, Majeed A.

Office for National Statistics, London.

This article examines trends in drug poisoning deaths involving antidepressant drugs between 1993 and 2002 in England and Wales as a whole and focuses particularly on the relationship between antidepressant prescribing and deaths in England. Between 1993 and 2002, age-standardised mortality rates in England and Wales decreased from about 9 to 7 per million population for both males and females. However, unlike females, rates in males rose to a peak of 12 per million in 1997 before declining. During the study period, the number of prescription items for antidepressants increased two and a half fold, largely due to increased use of selective serotonin re-uptake inhibitors and other antidepressants. Overall, death rates in England, per million prescription items, declined over the study period, with reductions in the rates for Dothiepin, Amitriptyline and all tricyclic antidepressants. There was no change in the rate for selective serotonin re-uptake inhibitors while rates for other antidepressants increased. Despite these trends, through all the study period rates were highest for tricyclic antidepressants and lowest for selective serotonin re-uptake inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15704381&dopt=Abstract antidepressant




Antidepressant-like effects of uridine and omega-3 fatty acids are potentiated by combined treatment in rats.

Carlezon WA Jr, Mague SD, Parow AM, Stoll AL, Cohen BM, Renshaw PF.

Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, USA. carlezon mclean.harvard.edu

BACKGROUND: Brain phospholipid metabolism and membrane fluidity may be involved in the pathophysiology of mood disorders. We showed previously that cytidine, which increases phospholipid synthesis, has antidepressant-like effects in the forced swim test (FST) in rats, a model used in depression research. Because cytidine and uridine both stimulate synthesis of cytidine 5'-diphosphocholine (CDP-choline, a critical substrate for phospholipid synthesis), we examined whether uridine would also produce antidepressant-like effects in rats. We also examined the effects of omega-3 fatty acids (OMG), which increase membrane fluidity and reportedly have antidepressant effects in humans, alone and in combination with uridine. METHODS: We first examined the effects of uridine injections alone and dietary supplementation with OMG alone in the FST. We then combined sub-effective treatment regimens of uridine and OMG to determine whether these agents would be more effective if administered together. RESULTS: Uridine dose-dependently reduced immobility in the FST, an antidepressant-like effect. Dietary supplementation with OMG reduced immobility when given for 30 days, but not for 3 or 10 days. A sub-effective dose of uridine reduced immobility in rats given sub-effective dietary supplementation with OMG. CONCLUSIONS: Uridine and OMG each have antidepressant-like effects in rats. Less of each agent is required for effectiveness when the treatments are administered together.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15705349&dopt=Abstract antidepressant




Antidepressant-associated chronic irritable dysphoria (acid) in bipolar disorder: a case series.

Ei-Mallakh RS, Karippot A.

Mood Disorders Research Program, Department of Psychiatry and behavioral Science, University of Louisville School of Medicine, Louisville, KY, USA. rselma01 athena.louisville.edu

BACKGROUND: Antidepressants administered to bipolar subjects may induce manias, mixed states, or rapid cycling. More recently, we have noted that long-term use of antidepressants may induce a chronic dysphoric, irritable state. METHOD: A case series is presented in which six type I bipolar subjects receiving antidepressants continuously for several years developed chronic irritable dysphoria. RESULTS: A triad of dysphoric mood, irritability, and middle insomnia that is frequently associated with occupational and social dysfunction can occur in some bipolar patients receiving antidepressants for at least 3 years. Typically, initial treatments with antidepressants for the index episode were effective. Over time, depressive symptoms returned and would transiently improve with dose increase or change of agents. Ultimately, the dysphoria and associated symptoms became chronic and resulted in dysfunction. Concomitant mood stabilizer did not appear to alter this pattern. Discontinuation of antidepressants was associated with a slow and gradual improvement in these symptoms over the ensuing year. CONCLUSION: Additional studies are required to investigate safety of long-term use of antidepressants in bipolar illness.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15708425&dopt=Abstract antidepressant




Women's views of antidepressants in the treatment of postnatal depression.

Boath E, Bradley E, Henshaw C.

Faculty of Health and Sciences, Staffordshire University, UK.

Little research has been carried out on the treatment of postnatal depression and clinicians must currently rely on general recommendations for the use of antidepressants. Antidepressant medication as the main treatment for depression in general practice has been shown to be effective when used as prescribed. However, research has shown that depressed patients consistently receive either no medication or consistently low doses of medication. This study will investigate women's experiences of taking antidepressant medication for postnatal depression. Thirty-five women with a clinical diagnosis of postnatal depression who had been prescribed antidepressant medication completed a questionnaire detailing their experiences of taking medication. Four open-ended questions and responses were discussed with the women. Of the 35 women who were prescribed medication, 4 chose not to take it because they were breast-feeding. Twenty of the women described finding medication helpful. Although only 4 women directly reported not taking antidepressants as prescribed, the comments made by a further 9 women suggest that compliance may have been poor. This study suggests a need to improve information about medication for postnatal depression. If this information is not provided, women are likely to continue to self-manage medication at a dosage that may be clinically ineffective.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15715021&dopt=Abstract antidepressant




Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study.

Martinez C, Rietbrock S, Wise L, Ashby D, Chick J, Moseley J, Evans S, Gunnell D.

General Practice Research Database Division, Medicines and Healthcare products Regulatory Agency, London SW8 5NQ.

OBJECTIVE: To compare the risk of non-fatal self harm and suicide in patients taking selective serotonin reuptake inhibitors (SSRIs) with that of patients taking tricyclic antidepressants, as well as between different SSRIs and different tricyclic antidepressants. DESIGN: Nested case-control study. SETTING: Primary care in the United Kingdom. PARTICIPANTS: 146,095 individuals with a first prescription of an antidepressant for depression. MAIN OUTCOME MEASURES: Suicide and non-fatal self harm. RESULTS: 1968 cases of non-fatal self harm and 69 suicides occurred. The overall adjusted odds ratio of non-fatal self harm was 0.99 (95% confidence interval 0.86 to 1.14) and that of suicide 0.57 (0.26 to 1.25) in people prescribed SSRIs compared with those prescribed tricyclic antidepressants. We found little evidence that associations differed over time since starting or stopping treatment. We found some evidence that risks of non-fatal self harm in people prescribed SSRIs compared with those prescribed tricyclic antidepressants differed by age group (interaction P = 0.02). The adjusted odds ratio of non-fatal self harm for people prescribed SSRIs compared with users of tricylic antidepressants for those aged 18 or younger was 1.59 (1.01 to 2.50), but no association was apparent in other age groups. No suicides occurred in those aged 18 or younger currently or recently prescribed tricyclic antidepressants or SSRIs. CONCLUSION: We found no evidence that the risk of suicide or non-fatal self harm in adults prescribed SSRIs was greater than in those prescribed tricyclic antidepressants. We found some weak evidence of an increased risk of non-fatal self harm for current SSRI use among those aged 18 or younger. However, preferential prescribing of SSRIs to patients at higher risk of suicidal behaviour cannot be ruled out.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15718538&dopt=Abstract antidepressant




The antidepressant-like effects of neurokinin NK1 receptor antagonists in a gerbil tail suspension test.

Varty GB, Cohen-Williams ME, Hunter JC.

CNS Biological Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. Geoffrey.Varty SPCorp.com

Recent clinical evidence supports the potential of neurokinin NK1 receptor antagonists as novel antidepressant drugs. A number of NK1 antagonists have reduced affinity for rat and mouse NK1 receptors compared to human, making it difficult to test for efficacy in traditional animal models. NK1 antagonists, in general, have similar affinity at gerbil and human NK1 receptors. The aims of these studies were first, to validate the gerbil tail suspension test, a test used frequently to demonstrate antidepressant drug efficacy in mice, and second, to determine whether the test could be used to demonstrate the antidepressant potential of NK1 antagonists. Immobility time was reduced by oral administration of the antidepressants imipramine (3-30 mg/kg), desipramine (1-30 mg/kg), amitriptyline (30 mg/kg), fluoxetine (1-30 mg/kg), paroxetine (3-10 mg/kg), citalopram (0.1-3 mg/kg), sertraline (1-30 mg/kg), venlafaxine (1-30 mg/kg) and nefazodone (100 mg/kg). Furthermore, oral administration of the NK1 antagonists MK-869 (10 mg/kg), L-742694 (10 mg/kg), L-733060 (10 mg/kg), CP-99994 (30 mg/kg), and CP-122721 (3-30 mg/kg) reduced immobility time. Diazepam (1-10 mg/kg), chlordiazepoxide (1-10 mg/kg), buspirone (3-30 mg/kg), FG-7142 (1-30 mg/kg), and haloperidol (1-10 mg/kg) did not reduce immobility. Amphetamine (0.3-10 mg/kg) and atropine (0.3-10 mg/kg) reduced immobility, suggesting susceptibility to false positives, e.g. compounds that affect locomotion. Compounds were therefore tested in a gerbil locomotor activity (LMA) test to ensure that the antidepressant-like effects were not secondary to effects on activity. Antidepressant drugs and NK1 antagonists had no effect on LMA at doses that reduced immobility, whereas amphetamine and atropine induced marked hyperactivity. These studies support both the utility of gerbils in behavioral pharmacology and the antidepressant potential of selective NK1 antagonists.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12576885&dopt=Abstract antidepressant