Jennifer L. Strauss

Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n=9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change=10.38) compared with patients receiving placebo (mean change=2.33), p=0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs=0.81, p=0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs=0.74, p=0.046). In addition, baseline pregnenolone (rs=−0.76, p=0.037), pregnenolone sulfate (rs=−0.83, p=0.015), and allopregnanolone levels (rs=−0.83, p=0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs=0.74, p<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.

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.

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.

The theoretical and empirical basis for meditation as an intervention for PTSD.

In spite of the existence of good empirically supported treatments for posttraumatic stress disorder (PTSD), consumers and providers continue to ask for more options for managing this common and often chronic condition. Meditation-based approaches are being widely implemented, but there is minimal research rigorously assessing their effectiveness. This article reviews meditation as an intervention for PTSD, considering three major types of meditative practices: mindfulness, mantra, and compassion meditation. The mechanisms by which these approaches may effectively reduce PTSD symptoms and improve quality of life are presented. Empirical evidence of the efficacy of meditation for PTSD is very limited but holds some promise. Additional evaluation of meditation-based treatment appears to be warranted.

Cerebrospinal Fluid Dehydroepiandrosterone Levels Are Correlated with Brain Dehydroepiandrosterone Levels, Elevated in Alzheimer’s Disease, and Related to Neuropathological Disease Stage

OBJECTIVE It is currently unknown whether cerebrospinal fluid (CSF) neurosteroid levels are related to brain neurosteroid levels in humans. CSF and brain dehydroepiandrosterone (DHEA) levels are elevated in patients with Alzheimers disease (AD), but it is unclear whether CSF DHEA levels are correlated with brain DHEA levels within the same subject cohort. We therefore determined DHEA and pregnenolone levels in AD patients (n = 25) and cognitively intact control subjects (n = 16) in both CSF and temporal cortex. DESIGN DHEA and pregnenolone levels were determined by gas chromatography/mass spectrometry preceded by HPLC. Frozen CSF and temporal cortex specimens were provided by the Alzheimers Disease Research Center at Duke University Medical Center. Data were analyzed by Mann-Whitney U test statistic and Spearman correlational analyses. RESULTS CSF DHEA levels are positively correlated with temporal cortex DHEA levels (r = 0.59, P < 0.0001) and neuropathological disease stage (Braak and Braak) (r = 0.42, P = 0.007). CSF pregnenolone levels are also positively correlated with temporal cortex pregnenolone levels (r = 0.57, P < 0.0001) and tend to be correlated with neuropathological disease stage (Braak) (r = 0.30, P = 0.06). CSF DHEA levels are elevated (P = 0.032), and pregnenolone levels tend to be elevated (P = 0.10) in patients with AD, compared with cognitively intact control subjects. CONCLUSIONS These findings indicate that CSF DHEA and pregnenolone levels are correlated with temporal cortex brain levels of these neurosteroids and that CSF DHEA is elevated in AD and related to neuropathological disease stage. Neurosteroids may thus be relevant to the pathophysiology of AD.

Allopregnanolone levels are reduced in temporal cortex in patients with Alzheimer's disease compared to cognitively intact control subjects.

The neurosteroid allopregnanolone has pronounced neuroprotective actions, increases myelination, and enhances neurogenesis. Evidence suggests that allopregnanolone dysregulation may play a role in the pathophysiology of Alzheimers disease (AD) and other neurodegenerative disorders. Our prior data demonstrate that allopregnanolone is reduced in prefrontal cortex in male patients with AD compared to male cognitively intact control subjects, and inversely correlated with neuropathological disease stage (Braak and Braak). We therefore determined if allopregnanolone levels are also reduced in AD patients compared to control subjects in temporal cortex, utilizing a larger set of samples from both male and female patients. In addition, we investigated if neurosteroids are altered in subjects who are APOE4 allele carriers. Allopregnanolone, dehydroepiandrosterone (DHEA), and pregnenolone levels were determined in temporal cortex postmortem samples by gas chromatography/mass spectrometry, preceded by high performance liquid chromatography (40 subjects with AD/41 cognitively intact control subjects). Allopregnanolone levels are reduced in temporal cortex in patients with AD (median 2.68 ng/g, n=40) compared to control subjects (median 5.64 ng/g, n=41), Mann-Whitney p=0.0002, and inversely correlated with Braak and Braak neuropathological disease stage (Spearman r=-0.38, p=0.0004). DHEA and pregnenolone are increased in patients with AD compared to control subjects. Patients carrying an APOE4 allele demonstrate reduced allopregnanolone levels in temporal cortex (Mann-Whitney p=0.04). In summary, our findings indicate that neurosteroids are altered in temporal cortex in patients with AD and related to neuropathological disease stage. In addition, the APOE4 allele is associated with reduced allopregnanolone levels. Neurosteroids may be relevant to the neurobiology and therapeutics of AD.

Interpersonal trauma, war zone exposure, and posttraumatic stress disorder among veterans with schizophrenia

The present study examined the prevalence of war zone exposure, interpersonal trauma and post-traumatic stress disorder (PTSD) in veterans with primary schizophrenia hospitalized on a VA inpatient psychiatric unit. Data were collected on a sample of male veterans (N=165) with a primary diagnosis of schizophrenia or schizoaffective disorder, who were consecutively admitted to a VAMC inpatient psychiatric unit. The prevalence of interpersonal trauma exposure and comorbid PTSD were assessed. Analyses also explored differences between those patients who had been identified with PTSD to those who screened positive but had not been previously identified as having PTSD. Ninety-six percent of the sample endorsed interpersonal trauma or exposure to a war zone. The prevalence of PTSD was 47% (n=78), although only 14% (n=11) of those who screened positive for PTSD had a diagnosis of PTSD in their medical record. Among those screening positive, having a chart diagnosis of PTSD was associated with more severe PTSD symptoms and combat exposure. Results suggest that PTSD is highly prevalent and under-diagnosed among veterans with schizophrenia. Increased assessment of trauma and PTSD in this population is warranted.

Erectile Dysfunction in Early, Middle, and Late Adulthood: Symptom Patterns and Psychosocial Correlates

The prevalence of erectile dysfunction (ED) increases with age. However, it may emerge at any time during the adult years, and may bear a close relationship to ongoing psychosocial issues affecting the patient and his partner. The present study examined ED symptomatology and its associated psychosocial context in 560 men aged 19-87 attending a urology clinic for erectile difficulties. We divided participants into three age groups: early adulthood (age 19-39); middle adulthood (40-59); and late adulthood (60+). They completed a self-report assessment battery evaluating medical, psychological, and lifestyle factors empirically or theoretically related to ED. Results showed that although younger men reported more positive overall ratings of their sex life and better overall erectile functioning relative to older men, they also reported comparatively less relationship satisfaction, greater depressive symptomatology, more negative reactions from partners, and less job satisfaction. Results suggest that older men experience less difficulty than younger men adjusting to life with ED.

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.

Lifetime sexual and physical victimization among male veterans with combat-related post-traumatic stress disorder.

ABSTRACT Because of the high prevalence of post-traumatic stress disorder (PTSD) among veteran men and the limited research on victimization in this group, we recruited 133 male veterans with combat-related PTSD from a psychiatric inpatient unit and assessed them for lifetime physical and sexual trauma. Results indicated that 96% of the sample had experienced some form of victimization over their lifetimes; 60% reported childhood physical abuse, 41% childhood sexual abuse, 93% adulthood physical assault, and 20% adulthood sexual assault. In the preceding year alone, 46% experienced either physical or sexual assault. These findings support the need for routine inquiry into the histories of noncombat victimization in this cohort. Determining the lifetime history of trauma exposure may have implications for vulnerability to subsequent development of PTSD and the risk of future violence.Because of the high prevalence of post-traumatic stress disorder (PTSD) among veteran men and the limited research on victimization in this group, we recruited 133 male veterans with combat-related PTSD from a psychiatric inpatient unit and assessed them for lifetime physical and sexual trauma. Results indicated that 96% of the sample had experienced some form of victimization over their lifetimes; 60% reported childhood physical abuse, 41% childhood sexual abuse, 93% adulthood physical assault, and 20% adulthood sexual assault. In the preceding year alone, 46% experienced either physical or sexual assault. These findings support the need for routine inquiry into the histories of noncombat victimization in this cohort. Determining the lifetime history of trauma exposure may have implications for vulnerability to subsequent development of PTSD and the risk of future violence.