Thomas L. Schwartz

Weight gain is a common side effect associated with antidepressant, anxiolytic, and antipsychotic drug use. Obesity is a risk factor for several other disorders, including hypertension, diabetes, and coronary artery disease. To date, there have been few safe, well-tolerated, and effective pharmacological agents available to alleviate weight gain in general, and virtually no studies specific to psychiatric drug-induced weight gain. This case series looks at the use of orlistat, a reversible inhibitor of lipases approved by the US Food and Drug Administration for obesity management, naturalistically in 13 patients with weight gain secondary to psychotropic drug use. The results showed that orlistat, administered in three daily doses with meals, was safe, well-tolerated, and effective, resulting in an average weight loss of 3–5% during an acute treatment period of about three months. Psychopharmacology Bulletin. 2003;37(1):5-9.

A majority of psychiatric medications are known to generate weight gain and ultimately obesity in some patients. There is much speculation about the prevalence of weight gain and the degree of weight gain during acute and longitudinal treatment with these agents. There is newer literature looking at the etiology of this weight gain and the potential treatments being used to alleviate this side effect. The authors undertook a comprehensive literature review in order to present epidemiology, etiology, and treatment options of weight gain associated with antipsychotics, mood stabilizers, and antidepressants.

Corcept Therapeutics Inc is developing mifepristone (as C-1073, Corlux), an orally available progesterone and glucocorticoid antagonist originally launched as an abortifacient by Aventis Pharma AG, for the potential treatment of the psychotic features of psychotic major depression (PMD) and for Alzheimer's disease (AD). In August 2004, a pivotal phase III trial was initiated in the US for psychotic features of PMD, a second trial began in October 2004 and these were followed by a European phase III trial in May 2005. However, in August 2006, September 2006 and March 2007, respectively, these phase III trials failed to meet their endpoints. A further phase III trial was to commence later in 2007. By August 2006, Corcept expected to file an NDA for PMD in 2007. In addition, in March 2005 a phase II study of mifepristone as a cognitive enhancer in AD was underway, and in May 2006 a proof-of-concept study in alleviating the weight gain associated with olanzapine had begun.

This study investigated tiagabine monotherapy in subjects with generalized anxiety disorder (GAD) who had been switched from selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) as a result of antidepressant-induced sexual dysfunction. Adults with DSM-IV GAD, an adequate therapeutic response (> or =50% decrease in Hamilton Rating Scale for Anxiety [HAM-A] total score) to SSRI or SNRI and sexual dysfunction were switched to open-label tiagabine 4-12 mg/day for 14 weeks. Assessments included the HAM-A, Hospital Anxiety & Depression Scale (HADS) and the Arizona Sexual Experiences Scale (ASEX); assessments were made at baseline and at Weeks 4, 8, and 14. Twenty six subjects were included in the analysis. Tiagabine showed no worsening in baseline symptoms of GAD, with non-significant changes from baseline in mean HAM-A total scores and HADS Anxiety and Depression subscale scores. There was a significant (p < 0.001) reduction in ASEX total scores from baseline following tiagabine, indicating an alleviation of sexual dysfunction. Tiagabine was reasonably tolerated; the most commonly reported adverse events were dizziness/light headedness (n = 6; 23%), nausea (n = 6; 23%) and fatigue (n = 2; 8%). Tiagabine may be useful in subjects who respond to previous antidepressant therapy but develop sexual dysfunction as an adverse event.

GABA has been implicated in both the aetiology and treatment of anxiety. Tiagabine is currently the only selective GABA reuptake inhibitor available in US markets; it exerts its action via GAT-1 transporter blockade presynaptically, facilitating GABA neurotransmission. Preclinical studies and current human studies suggest tiagabine possesses anxiolytic properties. The anxiolytic properties of tiagabine have also been suggested in a number of case series, open-label studies and placebo-controlled studies in patients with different anxiety disorders. Throughout these studies, tiagabine has been reasonably tolerated; the most commonly reported adverse events include dizziness, headache and nausea. Tiagabine may be a useful addition to currently available drugs for anxiety; however, the data from small open-label investigations remain to be confirmed in larger controlled studies.

Background: The objective of the study was to determine the genetic basis of Major Depressive Disorder, and the capacity to respond to antidepressant treatment. An association study of 21 candidate polymorphisms relevant to monoamine function and the mechanism of antidepressant response was conducted in 3 phenotypically distinct samples: a group with chronic or recurrent depression unable to respond to antidepressants (non-responders) (n = 58), a group capable of symptomatic improvement with or without treatment (responders) (n = 39), and volunteer controls (n = 85). The responders and non-responders constituted a larger group of depressed subjects.Methods: A candidate gene approach was employed to asses the genetics basis of Major Depressive Disorder. The genotypic frequencies of selected polymorphisms were compared between the controls and depressed subjects. To asses the genetics basis of the capacity to respond to antidepressant treatment, the responders were compared to the non-responders. Candidate genes were chosen based on functional studies and proximity to whole genome linkage findings in the literature. Risk genotypes were identified by previous functional studies and association studies.Results: A statistically significant difference in genotype frequency for theSLC6A4intron 2 VNTR was detected between the subjects with a history of depression and controls (p = 0.004). Surprisingly, a statistically significant difference was detected between responders and non-responders for theDRD4exon III VNTR genotype frequencies (p = 0.009). Furthermore, a difference between the controls and depressed subjects as well as between the controls and non-responders was detected for the number and distribution of risk genotypes in each group.Conclusion: An association between several monoamine-related genes and Major Depressive Disorder is supported. The data suggest that the two depressive phenotypes are genetically different, inferring that the genetic basis for the capacity to respond to standard antidepressant treatment, and the genetic susceptibility to Major Depressive Disorder may be independent. In addition, a proof of concept is provided demonstrating that the number of risk genotypes may be an indication of susceptibility of major depressive disorder and the severity of the disorder.

At least 50% of patients with anxiety disorders experience only partial response to pharmacotherapy and require augmentation therapy. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS, and agents that modulate GABA neurotransmission have shown promise in the treatment of anxiety disorders and are often used as augmentation agents. This study evaluated tiagabine, a selective GABA reuptake inhibitor (SGRI), as augmentation therapy. This 8-week, open-label study enrolled patients who remained symptomatic despite adequate drug trials for treatment of anxiety symptoms. Tiagabine augmentation therapy was initiated at 4 mg/d (taken in 2 doses; one in the morning with breakfast and one in the evening with a snack) for 2 days and increased to 8 mg/d for 10 days. Dose was then adjusted according to efficacy/tolerability in increments of 2 mg every 3 days up to a maximum of 20 mg/d. Effect was assessed using the Hamilton Rating Scale for Anxiety (HAM-A), Beck Anxiety Inventory (BAI), Clinical Global Impression (CGI) scale, Pittsburgh Sleep Quality Index (PSQI), and 36-item Short-Form Health Survey (SF-36). Of the 18 patients enrolled, 17 were included in the efficacy analysis; one withdrew due to an adverse event prior to post-baseline assessment. Mean final dose of tiagabine was 13 mg/d. Tiagabine as augmentation therapy further reduced anxiety symptoms, as shown by significant decreases in mean HAM-A total and BAI scores at Week 8 (P or =50% reduction in HAM-A total score), and 10 patients (59%) achieved remission (HAM-A total score < or =7) at Week 8. Tiagabine improved sleep quality, with a significant reduction seen in PSQI global score at Week 8 (P=.001). Augmentation therapy with tiagabine was generally well tolerated. These preliminary findings suggest that the SGRI tiagabine may be an effective and generally well tolerated augmentation therapy in patients with anxiety who remain symptomatic despite adequate drug trials for treatment of anxiety symptoms.

The original treatment indicated for those suffering from neurotic anxiety was to employ psychotherapy to facilitate changes in behavior and coping with stressful events. A spectrum of somatic treatments “from cathartics and emetics to opium and “strengthening tonics”, from atropine and digitalis to potassium bromide and chloral hydrate, from barbiturates to benzodiazepines”, to serotonergics, came to be used as well [1]. The Food and Drug Administration originally approved many gamma-aminobutyric acid (GABA) facilitating drugs since the 1960s for anxiety treatment. The 1980s evidenced the approval of a few serotonergic treatments that cornered the prescribing market and the front line of most treatment protocols. More recently, GABAergic drugs are making a return in the treatment of anxiety disorders. The following paper details the pharmacodynamic history of treating anxiety and also updates the reader as to the newer GABA-based approaches mentioned above.