Stephen M. Stahl

SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants.

The class of serotonin and norepinephrine reuptake inhibitors (SNRIs) now comprises three medications: venlafaxine, milnacipran, and duloxetine. These drugs block the reuptake of both serotonin (5-HT) and norepinephrine with differing selectivity. Whereas milnacipran blocks 5-HT and norepinephrine reuptake with equal affinity, duloxetine has a 10-fold selectivity for 5-HT and venlafaxine a 30-fold selectivity for 5-HT. All three SNRIs are efficacious in treating a variety of anxiety disorders. There is no evidence for major differences between SNRIs and SSRIs in their efficacy in treating anxiety disorders. In contrast to SSRIs, which are generally ineffective in treating chronic pain, all three SNRIs seem to be helpful in relieving chronic pain associated with and independent of depression. Tolerability of an SNRI at therapeutic doses varies within the class. Although no direct comparative data are available, venlafaxine seems to be the least well-tolerated, combining serotonergic adverse effects (nausea, sexual dysfunction, withdrawal problems) with a dose-dependent cardiovascular phenomenon, principally hypertension. Duloxetine and milnacipran appear better tolerated and essentially devoid of cardiovascular toxicity.

The metabolic syndrome and schizophrenia.

Objective:  To summarize the accumulated data on metabolic syndrome prevalence in patients with schizophrenia, examine evidence for a biological contribution of the mental illness to metabolic risk and review novel options available for management of prediabetic states.

Which comes first: atypical antipsychotic treatment or cardiometabolic risk?

Objective:  To provide an overview for practicing clinicians on the pharmacological basis of cardiometabolic risk induced by antipsychotic drugs in patients with serious mental illness, to propose hypotheses to explain these risks and to give tips for managing cardiometabolic risk during antipsychotic treatment.

The many faces of fatigue in major depressive disorder.

Fatigue is a common complaint in the community and medical care settings. Different studies show a high comorbidity between fatigue and depressive disorder. Furthermore, fatigue is an important somatic symptom of depressive disorder and one of the main depressive presentations in primary-care medicine. Fatigue shows a slow response to antidepressant treatment and psychotherapy. Improved work performance is strongly correlated to improvement in energy. However, the assessment and treatment of fatigue in depressive disorder remains understudied. Different definitions of fatigue in depressive disorder are applied in DSM-IV and ICD-10, and depression rating scales all show a different coverage of this core depressive symptom, thereby hampering scientific research. Serotonin, norepinephrine, dopamine and histamine mediate symptoms of fatigue in depressive disorder. Although few data address the effect of antidepressants or augmentation strategies on fatigue-related symptoms, there is a pharmacological rationale for using antidepressant monotherapies, such as venlafaxine, bupropion, sertraline, fluoxetine, or augmentation of first-line treatment with stimulants or modafinil.

Negative symptoms of schizophrenia: a problem that will not go away.

Objective:  Negative symptoms of schizophrenia are a common, enduring, and debilitating component of the psychopathology of schizophrenia. Although efforts thus far to elucidate a distinct schizophrenia subtype based upon negative symptoms have yielded mixed results, there are nevertheless neurobiological correlates of the negative symptom typology.

Mirtazapine: An Antidepressant with Noradrenergic and Specific Serotonergic Effects

Mirtazapine is a unique antidepressant that refines the specificity of effects on noradrenergic and serotonergic systems. It is an antagonist of presynaptic α2‐adrenergic autoreceptors and heteroreceptors on both norepinephrine and serotonin (5‐HT) presynaptic axons, plus is a potent antagonist of postsynaptic 5‐HT2 and 5‐HT3 receptors. The net outcome of these effects is increased noradrenergic activity together with specific increased serotonergic activity, especially at 5‐HT1A receptors. This mechanism of action maintains equivalent antidepressant efficacy but minimizes many of the adverse effects common to both tricyclic antidepressants and selective serotonin reuptake inhibitors. Mirtazapine has an onset of clinical effect in 2–4 weeks similar to other antidepressants, although sleep disturbances and anxiety symptoms may improve in the first week of treatment. It has minimal cardiovascular and anticholinergic effects, and essentially lacks serotonergic effects such as gastrointestinal symptoms, insomnia, and sexual dysfunction. Sedation, increased appetite, and weight gain are more common with mirtazapine than with placebo. An elimination half‐life of 20–40 hours enables once‐daily bedtime dosing. The recommended initial dosage is 15 mg once/day at bedtime, with an effective daily dosage range of 15–45 mg. Cases of overdose of up to 975 mg caused significant sedation but no cardiovascular or respiratory effects or seizures.

Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or cul-de-sac?

Objective:  Negative symptoms of schizophrenia are debilitating and they contribute to poor outcome in schizophrenia. Initial enthusiasm that second‐generation antipsychotics would prove to be powerful agents to improve negative symptoms has given way to relative pessimism that the effects of current pharmacological treatments are at best modest.

Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients with depression.

BACKGROUND Serotonergic and adrenergic enhancement may be synergistic and more effective than serotonergic enhancement alone in treating depression. The dual serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine is a dual reuptake inhibitor that may therefore offer greater efficacy than selective serotonin reuptake inhibitors (SSRIs). METHODS Data from eight randomized, double-blind, controlled studies were pooled to compare efficacy in depressed patients receiving venlafaxine/venlafaxine extended release (XR), SSRIs, or placebo for </=8 weeks. The mean changes from baseline in the 21-item Hamilton Rating Scale for Depression (HAM-D(21)), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impressions-Global Improvement (CGI-I) and CGI-Severity of Illness (CGI-S) item scores were compared, as were response rates derived from these scales. RESULTS Statistically significant differences in mean HAM-D(21) score decrease between venlafaxine (14.5) and SSRIs (12.6) and between the active treatments and placebo (11.3) were observed. Venlafaxine significantly decreased the mean MADRS scores more than SSRIs (17.8 vs. 15.9), and both treatments were significantly better than placebo (12.9). The same pattern of significance for CGI-I, HAM-D(21), and MADRS response rates between venlafaxine (71%, 64%, and 67%, respectively), SSRIs (64%, 57%, and 59%, respectively), and placebo (50%, 42%, and 41%, respectively) was observed. CONCLUSIONS Venlafaxine was significantly more effective than SSRIs in improving depression, perhaps due to enhancing both serotonin and norepinephrine.

Is Psychopharmacologic "Inoculation" Effective in Preventing Posttraumatic Stress Disorder?: (Brainstorms)

6 J Clin Psychiatry 66:1, January 2005 BRAINSTORMS is a monthly section of The Journal of Clinical Psychiatry aimed at providing updates of novel concepts emerging from the neurosciences that have relevance to the practicing psychiatrist. From the Neuroscience Education Institute in Carlsbad, Calif., and the Department of Psychiatry at the University of California San Diego. Reprint requests to: Stephen M. Stahl, M.D., Ph.D., Editor, BRAINSTORMS, Neuroscience Education Institute, 5857 Owens Street, Ste. 102, Carlsbad, CA 92009. W Is Psychopharmacologic “Inoculation” Effective in Preventing Posttraumatic Stress Disorder?

Agomelatine in the treatment of major depressive disorder: an 8-week, multicenter, randomized, placebo-controlled trial.

OBJECTIVE To evaluate the efficacy, safety, and tolerability of fixed-dose agomelatine 25 and 50 mg/d in the treatment of outpatients with moderate-to-severe major depressive disorder (MDD) compared to placebo. METHOD In this 8-week, multicenter, double-blind, parallel-group trial, patients with DSM-IV-defined MDD were randomly assigned (1:1:1) to receive a once-daily dose of agomelatine 25 mg, agomelatine 50 mg, or placebo. The primary efficacy measure was the change from baseline to week 8 in the clinician-rated 17-item Hamilton Depression Rating Scale (HDRS(17)); other efficacy measures were the clinical remission and response rates (measured by HDRS(17)), Clinical Global Impressions scales, Hospital Anxiety and Depression Scale (HADS) score, subjective measures on sleep, and the overall quality of life. The study was conducted between December 2006 and January 2008. RESULTS Agomelatine 25 mg/d was more efficacious based on the HDRS(17) total score (P = .01) compared to placebo throughout the treatment period, whereas for agomelatine 50 mg/d, statistically significant reduction in HDRS(17) total score could be observed from weeks 2 to 6 but not at week 8 (P = .144). A higher proportion of patients receiving agomelatine 25 mg/d showed clinical response (P = .013), clinical remission (P = .07), and improvement according to the Clinical Global Impressions-Improvement scale (P = .065) compared to those receiving placebo. No statistically significant difference between patients receiving agomelatine 50 mg/d compared to placebo on clinical response (P = .116) or clinical remission (P =. 457) was observed. HADS score, quality of sleep, and quality of life significantly improved with agomelatine 25 mg/d compared to placebo. Both agomelatine doses were safe and well tolerated, although clinically notable aminotransferase elevations were observed transiently in the agomelatine 50 mg/d group. CONCLUSIONS Agomelatine 25 mg/d was effective in the treatment of patients with moderate-to-severe MDD and was safe and well tolerated. Agomelatine 50 mg/d provided evidence for its antidepressant efficacy until week 6 and was also safe and well tolerated. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00411242.