Antidepressant Drugs and Patients with Psychotic Depression - Essay Example

Using rTMS and antidepressant drugs simultaneously to increase the therapeutic efficacy for patients with psychotic depression Summary It is estimated that in the next 10 years depression likely will be one of the more important causes of disability worldwide (Janicak et al., 2010). However, standard therapies are ineffective in a considerable proportion of depressive patients (Fava, 2003) while the existing treatment options are also often intolerable due to side effects (Janicak et al., 2010). Therefore, new biological therapies especially those involving application of rTMS and antidepressant drugs simultaneously need to be explored to potentially increase the therapeutic efficacy for patients with psychotic depression. Background Psychotic depression is a fairly common psychiatric condition that has been found to occur in nearly 20% of patients with major depression (Flores et al., 2006). The preferred treatment for psychotic depression so far has consisted of tricyclic antidepressants (TCAs) as also neuroleptic and electroconvulsive therapies (O’Neal et al., 2000). Patients with psychotic depression have a more severely disordered hypothalamic-pituitary-adrenocortical (HPA) axis (Kathol et al., 1989). The psychotic features of psychotic depression have been attributed also to excessive glucocorticoid activity (Schatzberg et al., 1985). Interestingly, HPA axis activity is, to a large extent, regulated by the combination of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) (Spencer et al., 1998; Young et al., 2003). Any mismatch between them could lead to inappropriate responses to stress, and incidence of major depression (Young et al., 2003). Decreases in MR sensitivity postulated to occur in major depression could result in elevated cortisol levels (Gesing et al., 2001; Young et al., 2003). In contrast, GR gives rise to feedback modifications in response to rising levels of cortisol as, for example, in response to stress or following the circadian rhythm. Hence, a GR antagonist e.g., the anti-progesterone steroid mifepristone (dimethylaminophenyl (17(-hydroxy-11(1(4-dimethylaminophenyl) 17(1- propynyl)estra-4,9-dien-3-one) exerts a powerful effect in the rising section of the HPA axis (Flores et al., 2006). A major effect of mifepristone occurs through obstruction of GR in crucial regions of the brain and in monaminergic nuclei, thereby, directly leading to recovery of symptomatic and cognitive faculties. First observed by Bickford et al.(1987) to trigger transient mood elevation in normal subjects receiving single-pulse stimulations to the motor cortex, the technique of non-invasive repetitive transcranial magnetic stimulation (rTMS) has been extensively studied, especially as adjunctive treatment for drug-resistant patients (George et al., 1995, 2000; Klein et al., 1999; Padberg et al., 1999; Berman et al., 2000; Grunhaus et al., 2003; Fitzgerald et al., 2003, 2006; Bortolomasi et al., 2007; Schönfeldt Lecuona et al., 2010). Hypothesis Application of rTMS as augmentation strategy to antidepressant treatment has yielded promising results (Rossini et al., 2005; Bretlau et al., 2008). The hypothesis is that antidepressants and rTMS may share some common mechanism of action at some common regions in the brain that would lead to augmentation of the antidepressant effect. There is compelling evidence to show that rTMS, in a manner similar to antidepressant drugs e.g., mifepristone, affects the activity of the hypothalamic-pituitary-adrenocortical system (Post and Keck, 2001). Also, since rTMS has substantially fewer side effects (Slotema et al., 2010), it is anticipated that the proposed treatment will be successful. Design & Methods. The study will be conducted over a period of 6 weeks on 75 adult patients of either sex with a diagnosis of major depression without comorbidity, recruited from the outpatient department. Elderly patients and patients with significant medical illnesses, neurological disorders, or other axis I psychiatric disorders will be excluded. Written informed consent will be obtained from all patients on a standard form. The subjects will be divided into 3 groups: (1) Active rTMS + antidepressant medication group, (2) Sham rTMS + antidepressant medication group, and (3) Active rTMS + placebo group. The antidepressant medication will consist of mifepristone (600 mg/day) whose clinical and biological effects are reported to be comparable among males and females (Flores et al., 2006). No studies so far have compared the combined efficacy of rTMS and mifepristone on the treatment of psychotic depression. Both rTMS and mifepristone affect the activity of the hypothalamic-pituitary-adrenocortical system. rTMS application will consist of bilateral, sequentially applied high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex which has been found to have substantial treatment efficacy in patients with treatment-resistant major depression (Fitzgerald et al., 2006). Clinical assessment will consist of the score on the Montgomery-Åsberg Depression Rating Scale for Depressed Subjects (MADRS) as well as the 17-item version of the Hamilton Depression Rating Scale (HAM-D). Patients showing >50% reduction in MADRS score will be considered to have met the response criteria and those with a final MADRS score of Read More