Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence.

Emerging preclinical and clinical evidence suggests that pregnenolone may be a promising novel therapeutic candidate in schizophrenia. Pregnenolone is a neurosteroid with pleiotropic actions in rodents that include the enhancement of learning and memory, neuritic outgrowth, and myelination. Further, pregnenolone administration results in elevations in downstream neurosteroids such as allopregnanolone, a molecule with neuroprotective effects that also increases neurogenesis, decreases apoptosis and inflammation, modulates the hypothalamic-pituitary-adrenal axis, and markedly increases GABA(A) receptor responses. In addition, pregnenolone administration elevates pregnenolone sulfate, a neurosteroid that positively modulates NMDA receptors. There are thus multiple mechanistic possibilities for pregnenolone as a potential therapeutic agent in schizophrenia, including the amelioration of NMDA receptor hypofunction (via metabolism to pregnenolone sulfate) and the mitigation of GABA dysregulation (via metabolism to allopregnanolone). Additional evidence consistent with a therapeutic role for pregnenolone in schizophrenia includes neurosteroid changes following administration of certain antipsychotics in rodent models. For example, clozapine elevates pregnenolone levels in rat hippocampus, and these increases may potentially contribute to its superior antipsychotic efficacy [Marx et al. (2006a) Pharmacol Biochem Behav 84:598-608]. Further, pregnenolone levels appear to be altered in postmortem brain tissue from patients with schizophrenia compared to control subjects [Marx et al. (2006c) Neuropsychopharmacology 31:1249-1263], suggesting that neurosteroid changes may play a role in the neurobiology of this disorder and/or its treatment. Although clinical trial data utilizing pregnenolone as a therapeutic agent in schizophrenia are currently limited, initial findings are encouraging. Treatment with adjunctive pregnenolone significantly decreased negative symptoms in patients with schizophrenia or schizoaffective disorder in a pilot proof-of-concept randomized controlled trial, and elevations in pregnenolone and allopregnanolone post-treatment with this intervention were correlated with cognitive improvements [Marx et al. (2009) Neuropsychopharmacology 34:1885-1903]. Another pilot randomized controlled trial recently presented at a scientific meeting demonstrated significant improvements in negative symptoms, verbal memory, and attention following treatment with adjunctive pregnenolone, in addition to enduring effects in a small subset of patients receiving pregnenolone longer-term [Savitz (2010) Society of Biological Psychiatry Annual Meeting New Orleans, LA]. A third pilot clinical trial reported significantly decreased positive symptoms and extrapyramidal side effects following adjunctive pregnenolone, in addition to increased attention and working memory performance [Ritsner et al. (2010) J Clin Psychiatry 71:1351-1362]. Future efforts in larger cohorts will be required to investigate pregnenolone as a possible therapeutic candidate in schizophrenia, but early efforts are promising and merit further investigation. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Comorbid posttraumatic stress disorder is associated with suicidality in male veterans with schizophrenia or schizoaffective disorder.

The purpose of this study was to determine if patients with schizophrenia or schizoaffective disorders and comorbid posttraumatic stress disorder (PTSD) are at higher risk for suicidality than patients without comorbid PTSD. Participants were 165 male veterans with primary diagnoses of schizophrenia or schizoaffective disorder. Those with comorbid PTSD reported higher rates of suicidal ideation and suicidal behaviors compared to those without comorbid PTSD. These findings suggest that patients with comorbid PTSD are at higher risk for suicidality. Enhanced screening and targeted interventions may be warranted to address comorbid PTSD and increased suicide risk in this population.

Comparison of two treatments for traumatic stress: a community-based study of EMDR and prolonged exposure.

This pilot study compared the efficacy of two treatments for postraumatic stress disorder (PTSD): Eye Movement Desensitization and Reprocessing (EMDR) and Prolonged Exposure (PE). Data were analyzed for 22 patients from a university-based clinic serving the outside community (predominantly rape and crime victims) who completed at least one active session of treatment after three preparatory sessions. Results showed both approaches produced a significant reduction in PTSD and depression symptoms, which were maintained at three-month follow-up. Successful treatment was faster with EMDR as a larger number of people (7 of 10) had a 70% reduction in PTSD symptoms after three active sessions compared to 2 of 12 with PE. EMDR appeared to be better tolerated as the dropout rate was significantly lower in those randomized to EMDR versus PE (0 of 10 vs. 3 of 10). However all patients who remained in treatment with PE had a reduction in PTSD scores. Finally, Subjective Units of Distress (SUDS) ratings decreased significantly during the initial session of EMDR, but changed little during PE. Postsession SUDS were significantly lower for EMDR than for PE. Suggestions for future research are discussed.

Dynamic systems theory as a paradigm for the study of change in psychotherapy: an application to cognitive therapy for depression.

Dynamic systems theory provides a conceptual framework for the study of change in psychotherapy that is consistent with that used in other sciences. A dynamic systems model of change was proposed and evaluated in the context of cognitive therapy for depression. Consistent with this model, less client protection and more destabilization of depressive patterns predicted more improvement at the end of treatment. Less protection was associated with more therapist support/stabilization. More destabilization was associated with more affective intensity in the session and with more of a therapist focus on the historical antecedents of current problems, exposure to multiple sources of corrective information, and repeated practice of new skills. Although preliminary, this pattern of findings is consistent with the model proposed and with principles of dynamic systems from other sciences.