Neurosteroid Changes Research Articles

19. Randomized Controlled Trial of a Neurosteroid Intervention in Schizophrenia

Abstract Background: Neurosteroids are endogenous molecules synthesized de novo in brain, adrenals, and other tissues. They demonstrate pleiotropic actions that are highly relevant to the neurobiology of schizophrenia. Clozapine markedly elevates neurosteroids in rodent hippocampus, potentially contributing to its superior therapeutic efficacy. Clinical evidence from a randomized controlled trial (RCT) conducted in Singapore suggests that pregnenolone significantly enhances functional capacity (as demonstrated by improvements in the UPSA Total Score and UPSA Communication Subscale Score) and that neurosteroid changes posttreatment predict therapeutic response (Marx et al 2014; Psychopharmacology). We thus conducted an RCT investigating adjunctive pregnenolone in schizophrenia. Methods: After a 2-week placebo lead-in, 88 participants with schizophrenia were randomized to pregnenolone (n = 42) or placebo (n = 46) for 8 weeks. Neurosteroids were quantified at baseline and posttreatment by mass spectrometry. Functional end points included the UPSA Total Score and UPSA Communication Subscale. Cognitive end points included the MCCB Composite Score and MCCB Subscales. Modified intent-to-treat analyses were conducted. Results: Participants randomized to the pregnenolone group did not outperform placebo on the UPSA Total Score or MCCB Composite Score. However, the pregnenolone group demonstrated significantly greater improvement in the UPSA Communication Subscale compared to participants randomized to placebo (P = .034), replicating prior RCT findings from Singapore. Elevations in pregnenolone post-treatment also predicted improvements in UPSA Total Score (r = .373; P = .039), again replicating prior efforts. In addition, the pregnenolone group demonstrated significantly greater improvement in the MCCB Verbal Learning Subscale compared to placebo (P = .023). Pregnenolone did not outperform placebo in the BACS Composite Score, SANS Total Score, or PANSS Total Score. Pregnenolone was well tolerated. Conclusion: Treatment with pregnenolone appears to improve functional capacity in a US population with schizophrenia, as assessed by the UPSA Communication Subscale and also supported by a significant positive correlation between pregnenolone changes and UPSA Total Score improvements—thus replicating findings from a prior RCT conducted in Singapore. Pregnenolone may also improve verbal memory. Given the positive correlation between pregnenolone increases posttreatment and UPSA Total Score improvements, it is possible that higher doses of pregnenolone may be clinically efficacious, and that neurosteroid quantification has biomarker potential for the predication of therapeutic response. Additional dose-finding investigations will be required to test these hypotheses. A pregnenolone decanoate formulation is currently in preclinical development.

No evidence of androgenic neurosteroid involvement in pediatric OCD

Certain androgenic neurosteroids have been shown to have a relationship with anxiety disorders in adults. Demonstrating these changes in pediatric patients as well is important in terms of elucidating the etiology of these disorders. The aim of this study was to investigate the testosterone, DHEA-S and cortisol levels in pediatric obsessive-compulsive disorder (OCD) patients. A total of 39 pediatric OCD patients aged 7–16 years and 34 healthy children of similar age and gender were included in this study. Serum total testosterone, DHEA-S and cortisol levels were measured by using the ELISA method and their relationship with clinical data was investigated. No statistically significant difference was found between the patient and control groups in terms of testosterone, DHEA-A and cortisol levels in the analyses performed (p=0.175, p=0.642, p=0.842, respectively). The results of this first study have revealed that testosterone, DHEA-S and cortisol levels in pediatric OCD patients are not different than in the controls. However, the fact that these neurosteroid levels have been found to differ between adult patients and controls previously indicates that neurosteroid changes may be a finding that appears during the course of anxiety disorders.

Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia.

Preclinical and clinical data suggest that pregnenolone may be a promising therapeutic in schizophrenia. Pregnenolone is neuroprotective and enhances learning and memory, myelination, and microtubule polymerization. Treatment with pregnenolone elevates allopregnanolone (a neurosteroid that enhances GABAA receptor responses) and pregnenolone sulfate (a positive NMDA receptor modulator). Pregnenolone could thus potentially mitigate GABA dysregulation and/or NMDA receptor hypofunction in schizophrenia via metabolism to other neurosteroids. The objective of this study is to conduct a randomized controlled trial of adjunctive pregnenolone in schizophrenia. Following a placebo lead-in, 120 participants were randomized to pregnenolone or placebo for 8 weeks (Institute for Mental Health, Singapore). Primary endpoints were changes in MATRICS Consensus Cognitive Battery (MCCB) composite scores (cognitive symptoms), UCSD Performance-based Skills Assessment-Brief (UPSA-B) composite scores (functional capacity), and Scale for Assessment of Negative Symptoms (SANS) total scores (negative symptoms). A modified intent-to-treat analysis approach was utilized. No significant changes compared to placebo were demonstrated in composite MCCB scores. In contrast, participants randomized to pregnenolone (n = 56) demonstrated greater improvements in functional capacity (UPSA-B composite changes) compared to placebo (n = 55), p = 0.03. Pregnenolone was also superior to placebo in the communication subscale of the UPSA-B (p < 0.001). Serum pregnenolone changes post-treatment were correlated with UPSA-B composite score changes in females (r s = 0.497, p < 0.042, n = 17) but not in males. Mean total SANS scores were very low at baseline and did not improve further post-treatment. Pregnenolone was well-tolerated. Pregnenolone improved functional capacity in participants with schizophrenia, but did not improve cognitive symptoms over an 8-week treatment period. Neurosteroid changes correlated with functional improvements in female participants. Neurosteroid interventions may exhibit promise as new therapeutic leads for 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.

Neurosteroid and GABA-A receptor alterations in Alzheimer's disease, Parkinson's disease and multiple sclerosis

Steroid hormones (e.g. estrogens, androgens, progestagens) which are synthesized de novo or metabolized within the CNS are called neurosteroids. There is substantial evidence from animal studies suggesting that these steroids can affect brain function by modulating neurotransmission, and influence neuronal survival, neuronal and glial differentiation and myelination in the CNS by regulating gene expression of neurotrophic factors and anti-inflammatory molecules. Indeed, evidence is emerging that expression of the enzymes responsible for the synthesis of neurosteroids changes in neurodegenerative diseases. Some of these changes may contribute to the pathology, while others, conversely, may represent an attempted rescue program in the diseased brain. Here we review the data on changes in neurosteroid levels and neurosteroid synthesis pathways in the human brain in three neurodegenerative conditions, Alzheimers's (AD) and Parkinson's (PD) diseases and Multiple Sclerosis (MS) and the extent to which these findings may implicate protective or pathological roles for neurosteroids in the course of these diseases.Some neurosteroids can modulate neurotransmitter activity, for example, the pregnane steroids allopregnanolone and 3α5α-tetrahydro-deoxycorticosterone which are potent positive allosteric modulators of ionotropic GABA-A receptors. Therefore, neurosteroid-modulated GABA-A receptor subunit alterations found in AD and PD will also be discussed. These data imply an involvement of neurosteroid changes in the neurodegenerative and neuroinflammatory processes and suggest that they may deserve further investigation as potential therapeutic agents in AD, PD and MS. Finally, suggestions for therapeutic strategies will be included. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Neurosteroids and Hepatic Encephalopathy: An Update on Possible Pathophysiologic Mechanisms

Cerebral complications of liver failure either due to chronic or acute manifestations lead to a neurological disorder known as Hepatic encephalopathy (HE). Neurosteroids, synthesized in the brain mainly by astrocytes but also in other brain cells independently from peripheral steroidal sources such as adrenal and gonads, are suggested to play a role in the pathogenesis of HE. The mechanisms by which neurosteroids affects brain function are not totally elucidated but may involve both genomic and non genomic effects. On one hand, neurosteroids bind and modulate different types of neuronal membrane receptors. While neurosteroid may affect directly postsynaptic receptors including GABA(A), 5-HT3, NMDA, glycine, and opioid receptors which have been involved in HE, neurosteroids effects through GABA(A) receptors may also compromise indirectly the function of neurons networking with GABAergic interneurons. On the other hand, some neurosteroids bind to intracellular receptors through which they also regulate gene expression, and there is substantial evidence confirming that expression of genes coding for key astrocytic and neuronal proteins are altered in HE. The mechanisms that trigger brain neurosteroid changes in HE are not yet well-known, but could involve (i) ammonia and manganese (in chronic HE)-induced translocator protein (TSPO) activation, (ii) neuroinflammation or (iii) blood-brain transfer of lipophylic neuroactive steroids. The present review summarizes evidence for the involvement of neurosteroids in HE and possible mechanisms for their altered brain production and central effects in human and experimental HE.

Circulating levels of neuroactive steroids in patients with binge eating disorder: a comparison with nonobese healthy controls and non-binge eating obese subjects.

Increased plasma levels of allopregnenolone (3alpha,5alpha-tetrahydroprogesterone [3alpha,5alpha-THP]), dehydroepiandrosterone (DHEA), and DHEA sulphate (DHEA-S) have been reported in patients with anorexia nervosa or bulimia nervosa. To assess whether those changes are related to malnutrition, we investigated plasma levels of neuroactive steroids in women with binge eating disorder (BED) who compulsively binge as bulimic patients, but do not incur malnutrition. Sixty-eight women participated in the study (31 nonobese healthy controls, 9 nonobese patients with BED, 16 obese patients with BED, and 12 obese non-binge eating women). Blood samples were collected in the morning for determination of plasma levels of 3alpha,5alpha-THP, DHEA, DHEA-S, and cortisol. Nonobese BED women had significantly higher plasma levels of DHEA, DHEA-S, and 3alpha,5alpha-THP than nonobese healthy women. Similarly, obese individuals with BED exhibited significantly higher neurosteroid plasma levels than non-binge eating obese subjects. No significant differences in plasma cortisol levels were observed among the groups. This study shows increased plasma levels of neuroactive steroids in BED patients. These findings could have been influenced by methodologic limitations (e.g., the absence of diurnal sampling). However, they suggest that if malnutrition is involved in the determination of increased plasma levels of neuroactive steroids in people with anorexia or bulimia nervosa, then different factors may induce similar effects in people with BED. Alternatively, common unknown factors could be responsible for neurosteroid changes in anorexia nervosa, bulimia nervosa, and BED.