B.R. Slaap

Serotonergic drugs in the treatment of depressive and anxiety disorders

Serotonergic dysfunction has been implicated in the aetiology of several psychiatric conditions, including depressive and anxiety disorders. Much of the evidence for the role of serotonin (5‐HT) in these disorders comes from treatment studies with serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs), 5‐HT1A agonists and 5‐HT antagonists. This review considers the place of these drugs in the treatment of panic disorder, obsessive‐compulsive disorder (OCD), social phobia, and generalized anxiety disorder (GAD). Among these agents, the SSRIs stand out with proven efficacy in the treatment of a spectrum of disorders, such as depression, panic disorder, OCD and social phobia. They may also be a suitable treatment for GAD. 5‐HT1A agonists have been used extensively for the treatment of depression and GAD but evidence of their efficacy in other anxiety disorders is equivocal. 5‐HT antagonists are the least well studied of these agents: while they may have activity in depression, their efficacy has not been fully investigated in anxiety disorders. However, preliminary reports suggest that they may be useful as adjuvants to SSRIs in treatment‐refractory OCD. The high incidence of comorbidity amongst psychiatric disorders means that pharmacotherapy that is effective against a range of disorders, such as the SSRIs, is of considerable use to clinicians. Future research into the biological mechanisms underlying such disorders is likely to further enhance pharmacotherapy. Copyright

Review of current treatment in panic disorder

The ideal properties tor an antipanic agent include the ability to provide complete recovery from panic attacks, resolution of associated anxiety and avoidance behavior, relapse prevention, good tolerability, and efficacy in comorbid conditions including depression. We compared the properties of currently available treatment options for panic attacks, including the benzodiazepines, tricyclic antidepressants, monoamine oxidase inhibitors and selective serotonin reuptake inhibitors (SSRIs), with this ideal. Experimental approaches in the development of therapeutic agents of potential use against panic disorder were also examined. It is clear that SSRIs, such as paroxetine, are an effective treatment for panic disorder, and their antidepressant activity also allows concurrent treatment of comorbid depressive disorders, for which patients with panic disorder are at high risk. However, despite the availability of effective antipanic agents, some patients do not respond to treatment.

Responders and non-responders to drug treatment in social phobia: differences at baseline and prediction of response

Differences between responders and non-responders to drug therapy were investigated in social phobia. Two previously published studies were pooled to obtain data of 30 patients who were treated for 12 weeks with brofaromine or fluvoxamine. Four criterion variables were used to divide patients in responders and non-responders. Depending on the criterion variable up to 72% of the patients were regarded as responders. Non-responders differed from responders in that they had a higher heart rate and a higher blood pressure. They were also characterized by higher scores on several psychometric scales, indicative of illness severity.

The effect of mirtazapine in panic disorder: an open label pilot study with a single-blind placebo run-in period

In this open label pilot study, we studied the efficacy of mirtazapine (Remeron) in panic disorder. Twenty-eight patients with a DSM-IV diagnosis of panic disorder, with or without agoraphobia (10 males/18 females), were included and 19 patients completed the study. The 15-week trial started with a 3-week single-blind placebo run-in period. After this run-in period, the 12-week active treatment phase started. As primary efficacy measures, we studied the decrease in the number of full symptom panic attacks and the number of patients completely free of panic during the last 3 weeks of the study. Seventy-four percent of the patients were considered responders, according to a decrease of at least 50% in panic attack frequency. All primary and secondary efficacy measures showed a significant improvement from the second week of active treatment onwards to endpoint. The main side-effects were different from the usual side-effects in selective serotonin reuptake inhibitors (SSRIs) (initial drowsiness, weight gain and pain in the legs). The results of this open label study in panic disorder suggest that mirtazapine seems to be a fast and effective treatment alternative for SSRIs in panic disorder.

Behavioral, neuroendocrine and biochemical effects of different doses of 5-HTP in panic disorder

To investigate the role of serotonin (5-HT) in the pathophysiology of panic disorder (PD) a challenge test with L-5-hydroxytryptophan (5-HTP) was conducted. Seven patients suffering from PD and seven healthy controls received an i.v. challenge with 10 mg, 20 mg and 40 mg 5-HTP and placebo in random order on four different occasions. Before, during and until 2 h after 5-HTP administration anxious and depressive symptomatology was assessed. In addition, plasma levels of 5-HTP, cortisol, and 5-HIAA were measured at several timepoints. During and after infusion of placebo or any of the different dosages of 5-HTP, none of the patients or controls experienced a panic attack or showed an increase in anxiety or depressive symptoms. There was a dose-related increase in side effects, like nausea, dizziness and fatigue. Only infusion with 40 mg 5-HTP led to an increase in plasma cortisol in both patients and controls. The observed increase in plasma cortisol level was higher for patients compared to controls only at 30 min after infusion. In conclusion, stimulation of the serotonergic neuronal system by three different dosages of 5-HTP did not induce panic or anxiety in PD patients and healthy controls. The 5-HT hypersensitivity hypothesis of PD could not be confirmed in the present study.

Phobic symptoms as predictors of nonresponse to drug therapy in panic disorder patients (a preliminary report)

Factors that predict nonresponse to drug therapy (brofaromine or fluvoxamine) were investigated in a sample of 44 panic disorder patients. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment. Using this definition, 15 patients (32.6%) were considered nonresponders. Nonresponders had a higher score on the Blood-Injury subscore of the Fear Questionnaire (FQ) and more often had high scores on several FQ subscores, indicative of comorbid phobic symptoms. These variables were subsequently used to predict nonresponse.

MHPG and heart rate as correlates of nonresponse to drug therapy in panic disorder patients

Little is known about biological predictors of treatment response in panic disorder (PD). In the present study heart rate, blood pressure, plasma cortisol and plasma MHPG were investigated at baseline in a sample of 44 PD patients as possible predictors for nonresponse to treatment. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment with brofaromine or fluvoxamine. Patients were considered nonresponders when they fulfilled two criteria: they did not show a 50% reduction of agoraphobic avoidance and they still experienced panic attacks at endpoint. The variables that differed significantly between the groups were used to predict nonresponse to drug therapy. Using this strict definition of nonresponse, 15 patients (32.6%) were considered nonresponders. These patients were characterised by a higher plasma MHPG concentration and a higher heart rate at baseline. These variables were subsequently used to predict nonresponse.

Meta-analyses of efficacy of asenapine in bipolar I disorder as monotherapy and adjunct therapy compared with other atypical antipsychotics

Objective: Asenapine has been reported to be efficacious in the treatment of acute manic or mixed episodes, both as a monotherapy and as adjunctive therapy in patients with incomplete response to lithium or valproate. Asenapine is approved in the European Union for the treatment of moderate to severe manic episodes in bipolar I disorder. We performed a meta-analyses of asenapine placebocontrolled trials to further determine the efficacy of asenapine for acute bipolar mania and to compare asenapine with other atypical antipsychotics.