The Effect of Dehydroepiandrosterone Administration during Rehabilitation on White Matter Integrity Among Individuals With Polysubstance Use Disorder.

OBJECTIVES: Individuals with polysubstance use disorder (pSUD) exhibit vulnerability to relapse even after prolonged abstinence, with rehabilitation efforts achieving limited success. Previous studies highlighted dehydroepiandrosterone (DHEA) as a putative therapeutic agent that may aid rehabilitation, potentially by impacting white matter (WM) properties. The current study tested, for the first time, the effect of DHEA administration during rehabilitation on WM integrity among pSUD individuals, while assessing its putative association with long-term relapse rates. METHODS: Immediately after admission to rehabilitation, 30 pSUD individuals were assigned to receive either placebo or DHEA (100 mg) daily for 3 months, via a randomized double-blind counterbalanced design. Participants also provided blood samples to assess circulating DHEA levels at treatment initiation and completed a diffusion tensor imaging (DTI) scan approximately 1 month after treatment initiation. Clinical status was evaluated 16 months after treatment initiation. Thirty matched healthy controls also underwent a DTI scan without any intervention. RESULTS: DHEA administration was not associated with reduced relapse rates compared with placebo. Nevertheless, exploratory analysis revealed that DHEA was associated with successful rehabilitation among pSUD individuals with low circulating DHEA levels at treatment initiation. White matter integrity in the splenium corpus callosum (CC) was reduced in pSUD individuals compared with healthy controls, yet pSUD individuals receiving DHEA exhibited recovery of splenium CC WM integrity. CONCLUSIONS: DHEA administration during rehabilitation may restore WM integrity in the CC among pSUD individuals. Although DHEA was not associated with reduced relapse rates in here, its therapeutic efficacy may depend on circulating DHEA levels at treatment initiation.

The Effect of Dehydroepiandrosterone Treatment on Neurogenesis, Astrogliosis and Long-Term Cocaine-Seeking Behavior in a Cocaine Self-Administration Model in Rats.

Cocaine addiction is an acquired behavioral state developed in vulnerable individuals after cocaine exposure. It is characterized by compulsive drug-seeking and high vulnerability to relapse even after prolonged abstinence, associated with decreased neurogenesis in the hippocampus. This addictive state is hypothesized to be a form of "memory disease" in which the drug exploits the physiological neuroplasticity mechanisms that mediate regular learning and memory processes. Therefore, a major focus of the field has been to identify the cocaine-induced neuroadaptations occurring in the usurped brain's reward circuit. The neurosteroid dehydroepiandrosterone (DHEA) affects brain cell morphology, differentiation, neurotransmission, and memory. It also reduces drug-seeking behavior in an animal model of cocaine self-administration. Here, we examined the long-lasting effects of DHEA treatment on the attenuation of cocaine-seeking behavior. We also examined its short- and long-term influence on hippocampal cells architecture (neurons and astrocytes). Using a behavioral examination, immunohistochemical staining, and diffusion tensor imaging, we found an immediate effect on tissue density and activation of astrocytes, which has a continuous beneficial effect on neurogenesis and tissue organization. This research emphasizes the requites concert between astrocytes and neurons in the rehabilitation from addiction behavior. Thus, DHEA may serve as a treatment that corrects brain damage following exposure to and abstinence from cocaine.

Chronic opipramol treatment extinguishes cocaine craving through Rac1 in responders: A rat model study.

Ras-related C3 botulinum toxin substrate 1 (Rac1), of the Rho small GTPase family, is a key regulator of actin cytoskeleton rearrangement and plays an important role in dendritic morphogenesis. Cocaine produces neuronal alterations, including structural changes in dendritic number and morphology. Emerging data indicate sigma-1 receptors (σ-1Rs) as a promising candidate for the prevention of cocaine craving. Opipramol is a σ-1R agonist approved in some European countries for depression and anxiety. Here we report that opipramol, mediated by Rac1, attenuates cocaine-seeking behavior in a rat model of self-administration. The opipramol effect was shown in two phases. It decreased cocaine-seeking behavior throughout the withdrawal phase and, interestingly, showed a significant reduction of cocaine-primed reinstatement in 75% of the opipramol-treated group (termed 'responders'). All opipramol-treated rats showed a decrease in σ-1R mRNA expression levels in the nucleus accumbens (NAc) versus controls. Responders also exhibited significantly decreased NAc Rac1 mRNA expression levels, compared with non-responder rats. Hence, Rac1 differentiated responders from non-responders. Rac1 correlated positively with σ-1R mRNA levels in opipramol responders. In another experiment, Rac1 inhibitor injected directly into the NAc core decreased active lever presses on the first day of extinction, indicating the critical role of Rac1 in the opipramol effect on drug seeking. We postulate that chronic activation of σ-1R, through a dynamic interaction with Rac1, may suggest a new approach to treat substance use disorder (SUD). Rac1 inhibition is a prerequisite for decreasing drug seeking and rehabilitation, and this can be achieved by opipramol, a medication that can be given during detoxification.

Novel Opipramol-Baclofen Combination Alleviates Depression and Craving and Facilitates Recovery From Substance Use Disorder-An Animal Model and a Human Study.

Substance use disorders (SUDs) are associated with depression and anxiety, with the latter being one of the major factors in substance-seeking and relapse. Due to dose-dependent sedative side effects there is limited efficacy of baclofen treatment for SUDs. Here we suggest the use of a novel combination of opipramol and baclofen (O/B) which is known to attenuate anxiety and depression, for the facilitation of recovery from SUDs. Since both opipramol and baclofen have a common downstream signal transduction, their individual doses could be reduced while still maintaining the benefits of the combination. We tested the O/B combination in both animals and patients. Rats treated with O/B showed significant attenuation in craving behavior and in relapse rate during withdrawal from cocaine. In a double-blind, placebo-controlled pilot study, conducted in a residential detoxification center, 14 males and 3 females, aged 28-60 years were assigned to a study (n = 6) and a placebo (n = 11) group (placebo group: 40 ± 10.5 years; O/B group 40 ± 10.8 years). The participants completed scales measuring depression, anxiety and craving symptoms and provided saliva samples for stress hormone examination [cortisol and dehydroepiandrosterone-sulfate (DHEA-S)]. Participants with polysubstance use disorder (PsUD) treated with O/B showed a reduction in cravings and depression and an increase in DHEA-S and in the DHEA-S/cortisol ratio. Our findings indicate a beneficial effect of O/B treatment. This study suggests a novel candidate for pharmacological treatment of patients with SUD and comorbid mood/anxiety disorders that may facilitate their rehabilitation.

A DNA Methylation Signature of Addiction in T Cells and Its Reversal With DHEA Intervention.

Previous studies in animal models of cocaine craving have delineated broad changes in DNA methylation profiles in the nucleus accumbens. A crucial factor for progress in behavioral and mental health epigenetics is the discovery of epigenetic markers in peripheral tissues. Several studies in primates and humans have associated differences in behavioral phenotypes with changes in DNA methylation in T cells and brain. Herein, we present a pilot study (n = 27) showing that the T cell DNA methylation profile differentiates persons with a substance use disorder from controls. Intervention with dehydroepiandrosterone (DHEA), previously shown to have a long-term therapeutic effect on human addicts herein resulted in reversal of DNA methylation changes in genes related to pathways associated with the addictive state.

Dehydroepiandrosterone and Addiction.

Drug addiction has a great negative influence on society, both social and economic burden. It was widely thought that addicts could choose to stop using drugs if only they had some self-control and principles. Nowadays, science has changed this view, defining drug addiction as a complex brain disease that affects behavior in many ways, both biological and psychological. Currently there is no ground-breaking reliable treatment for drug addiction. For more than a decade we are researching an alternative approach for intervention with drug craving and relapse to its usage, using DHEA, a well-being and antiaging food supplement. In this chapter we navigate through the significant therapeutic effect of DHEA on the brain circuits that control addiction and on behavioral performance both in animal models and addicts. We suggest that an integrative program of add-on DHEA treatment may further enable to dynamically evaluate the progress of rehabilitation of an individual patient, in a comprehensive assessment. Such a program may boost and support the detoxification and rehabilitation process, and help patients regain a normal life in a shorter amount of time.

Effect of dehydroepiandrosterone add-on therapy on mood, decision making and subsequent relapse of polydrug users.

A major problem in the treatment of addiction is predicting and preventing relapse following a rehabilitation program. Recently, in preclinical rodent studies dehydroepiandrosterone (DHEA) was found to markedly improve the resistance to drug reuse. In a double-blind, placebo-controlled study, we examined the effect of DHEA on relapse rates in adult polydrug users taking part in a detoxification program enriched with intensive psychosocial interventions and aftercare. During treatment, participants (79 percent males, mean age 28) consumed DHEA (100 mg/day) or placebo daily for at least 30 days. Of the 121 initial volunteers, 64 participated for at least 1 month. While in treatment, DHEA reduced negative affect on the Positive and Negative Affect Scale (F = 4.25, P = 0.04). Furthermore, in a 16-month follow-up, we found that reuse rates in the DHEA condition were about a third compared with placebo (12 versus 38 percent; χ(2) = 5.03, P = 0.02). DHEA treatment also resulted in an increase in DHEA sulfate (DHEA-S) 1 month following treatment, and the level of DHEA-S predicted relapse in the follow-up assessment.

The effect of reboxetine co-administration with olanzapine on metabolic and endocrine profile in schizophrenia patients.

RATIONALE: We previously demonstrated that the addition of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Using the same study sample, we also sought to determine whether reboxetine's weight-attenuating effect was accompanied by a beneficial effect on metabolic and endocrine parameters relevant to antipsychotic-induced weight gain and obesity. METHOD: Blood samples at baseline and at the end of the 6-week trial were available for 54 participants who participated in previous double-blind, placebo-controlled studies of reboxetine (4 mg BID) addition to olanzapine-treated schizophrenia patients. Fasting glucose, lipid profile, insulin, leptin, cortisol, dehydroepiandrosterone (DHEA), prolactin, and thyroid-stimulating hormone (TSH) were analyzed. RESULTS: In contrast to the olanzapine/placebo group, the olanzapine/reboxetine group exhibited a reduction in blood triglyceride (p < 0.05) and leptin (p < 0.05) levels, and elevation in cortisol (p < 0.05) and DHEA (p < 0.008) levels. No significant between-group differences were detected in the changes in cholesterol, glucose, insulin, TSH, and prolactin. CONCLUSIONS: Reboxetine addition resulted in meaningful improvement of some metabolic and endocrine measures associated with olanzapine-induced weight gain. The potential role of reboxetine in the prevention of olanzapine-induced weight gain and cardio-metabolic morbidity merits further large-scale, long-term investigation.

Neonatal stress modulates sickness behavior: role for proinflammatory cytokines.

Neonatal stress increased the duration and augmented symptoms of sickness behavior induced by influenza virus infection or endotoxin challenge in mice. Since proinflammatory cytokines were implicated in sickness behavior, the present study sought to determine the effect of neonatal stress on cytokines-induced sickness behavior and on proinflammatory cytokine secretion. Data indicate that separation of mouse pups from the dams at an early age (maternal separation, MSP) increased the duration and augmented some of the symptoms of sickness behavior induced by proinflammatory cytokines. In addition, MSP partially suppressed cytokine and corticosterone secretion in response to endotoxin administration. These data may suggest that MSP increased sensitivity to the effects of proinflammatory cytokines on sickness behavior following an immune challenge.

The influence of DHEA pretreatment on prepulse inhibition and the HPA-axis stress response in rat offspring exposed prenatally to polyriboinosinic-polyribocytidylic-acid (PIC).

Prenatal exposure to maternal infection may be associated with the development of neurodevelopmental disorders as well as increased susceptibility to the development of schizophrenia. Prenatal administration of polyriboinosinic-polyribocytidilic-acid, mimicking RNA virus exposure, has been shown to induce schizophrenia-like behavioral, neurochemical and neuorophysiological abnormalities in rodent offspring. In the present study PIC prenatal administration at gestation day 15 was associated with alterations in the acoustic-startle-response/prepulse-inhibition [ASR/PPI] and the HPA-axis stress response in rat offspring on day 90. We show that pretreatment with dehydroepiandrosterone (DHEA) reverses PIC-related ASR/PPI disruption in female rats and normalizes HPA-axis stress response in a united group of male and female rats. Further research in both animal and human studies is recommended in order to confirm these preliminary findings and their application to the understanding and management of schizophrenia and related conditions.

Serum levels of brain-derived neurotrophic factor and cortisol to sulfate of dehydroepiandrosterone molar ratio associated with clinical response to L-theanine as augmentation of antipsychotic therapy in schizophrenia and schizoaffective disorder patients.

OBJECTIVES: L-Theanine (γ-glutamylethylamide) augmentation to antipsychotic therapy ameliorates positive, activation, and anxiety symptoms in schizophrenia and schizoaffective disorder patients. This study examines the association between circulating levels of neurochemical indicators and the beneficial clinical effects of L-theanine augmentation. METHODS: Serum levels of neurochemical indicators such as brain-derived neurotrophic factor (BDNF), dehydroepiandrosterone (DHEA), its sulfate (DHEAS), cortisol, cholesterol, and insulin were monitored in 40 schizophrenia and schizoaffective disorder patients during an 8-week, double-blind, randomized, placebo-controlled trial with L-theanine (400 mg/d). Multiple regression analysis was applied for searching association between improvement in symptom scores and changes in circulating levels of neurochemical indicators for an 8-week trial. RESULTS: Regression models among L-theanine-treated patients indicate that circulating levels of BDNF and cortisol-to-DHEAS*100 molar ratio were significantly associated with the beneficial clinical effects of L-theanine augmentation. Variability of serum BDNF levels accounted for 26.2% of the total variance in reduction of dysphoric mood and 38.2% in anxiety scores. In addition, the changes in cortisol-to-DHEAS*100 molar ratio accounted for 30% to 34% of the variance in activation factor and dysphoric mood scores and for 15.9% in anxiety scores. Regression models among placebo-treated patients did not reach significant level. CONCLUSIONS: These preliminary results indicate that circulating BDNF and cortisol-to-DHEAS*100 molar ratio may be involved in the beneficial clinical effects of L-theanine as augmentation of antipsychotic therapy in schizophrenia and schizoaffective disorder patients.

Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia and schizoaffective disorder: an 8-week, double-blind, randomized, controlled, 2-center, parallel-group trial.

OBJECTIVE: Pregnenolone (PREG) and dehydroepiandrosterone (DHEA) are reported to have a modulatory effect on neuronal excitability, synaptic plasticity, and response to stress; they are associated with mood regulation and cognitive performance. We investigated the influence of PREG and DHEA on psychotic symptoms and cognitive functioning as an add-on to ongoing antipsychotic treatment of patients with chronic schizophrenia or schizoaffective disorder. METHOD: This 8-week, double-blind, randomized, placebo-controlled, 2-center study compared 30 mg/d of PREG (PREG-30), 200 mg/d of PREG (PREG-200), 400 mg/d of DHEA, and placebo as an adjunctive treatment of 58 chronic schizophrenia or schizoaffective disorder patients (DSM-IV). The data were collected from February 2005 until June 2007. The outcome measures were symptomatic and neurocognitive changes, functioning, and tolerability as assessed primarily by the Clinical Global Impressions-Severity of Illness scale and the Positive and Negative Syndrome Scale. Analyses are presented for 44 patients who completed 8 weeks of treatment and for 14 noncompleters. RESULTS: Compared with subjects who received placebo, those administered PREG-30 had significant reductions in positive symptom scores and extrapyramidal side effects (EPS) and improvement in attention and working memory performance, whereas subjects treated with PREG-200 did not differ on outcome variable scores for the study period. The general psychopathology severity and general functioning of patients receiving placebo and PREG-30 improved more than that of those subjects treated with DHEA, while EPS improved more in subjects treated with DHEA than in patients receiving placebo. Negative symptoms and akathisia were not significantly benefited by any treatment. The administration of PREG and DHEA was well tolerated. CONCLUSIONS: Low-dose PREG augmentation demonstrated significant amelioration of positive symptoms and EPS and improvement in attention and working memory performance of schizophrenia and schizoaffective disorder patients. Further double-blind controlled studies are needed to investigate the clinical benefit of pregnenolone augmentation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00174889.

The role of dehydroepiandrosterone (DHEA) in drug-seeking behavior.

Conventional substance-abuse treatments have only had limited success especially for drugs such as cocaine, methamphetamine and nicotine. Newer data have begun to shed light on the complexity of the addictive process and new treatment approaches, including interference with brain neurosteroids, to attenuate drug-seeking behavior, are in advanced stages of development. Neurosteroids are synthesized in the brain and peripheral tissues, from cholesterol or steroidal precursors imported from peripheral sources. The most abundant neurosteroids in the human body are DHEA and its sulfate ester, DHEAS. These neurosteroids can act as modulators of neurotransmitter receptors, such as γ-aminobutyric-acid-type A (GABA(A)), NMDA, and sigma-1 receptors which may contribute to apparent enduring behavioral manifestations facilitated by substances of abuse. Neurosteroid concentrations respond to environmental and behavioral circumstances, such as stress and mood, both which are involved in the progression of substance use that advance substance addiction. This article reviews the current literature pertaining to neurosteroids and substances of abuse, focusing on DHEA, and discusses its role in drug-seeking behavior as suggested by preclinical observations.

Effect of exposure to selective serotonin reuptake inhibitors in utero on fetal growth: potential role for the IGF-I and HPA axes.

To investigate the possible effect of fetal exposure to selective serotonin reuptake inhibitors (SSRIs) on somatic growth and on hormones of the hypothalamic-pituitary-adrenal (HPA) and insulin-like growth factor (IGF)-I axes, we compared the anthropometric parameters and hormonal profile of 21 SSRI-exposed infants and 20 matched controls. The SSRI group was characterized by lower crown-heel length (p < 0.01), smaller head circumference (p = 0.08), and higher percentage of infants with birth weight, birth length, and head circumference below the 10th percentile (p < 0.045, p = 0.08, p < 0.04, respectively), in addition to a significantly lower cord blood level of cortisol (p < 0.03) and higher level of thyroid-stimulating hormone (TSH) (p < 0.004). Infants exposed to citalopram had a lower cord blood IGF-I level than infants exposed to paroxetine (p < 0.001) and controls (p < 0.003). Placental IGF-I receptor (IGF-IR) expression was significantly higher in the SSRI group than in controls (p < 0.01). Urine 5-hydroxyindoleacetic acid (5-HIAA) level was negatively correlated with birth weight (r = -0.71, p < 0.025) and with dehydroepiandrosterone (DHEA) level (r = -0.71, p < 0.025). The Finnegan score was correlated with dehydroepiandrosterone sulfate (DHEAS) (r = 0.8, p < 0.005) and cortisol (r = 0.62, p = 0.05). Fetal exposure to SSRIs causes impaired intrauterine growth accompanied by alterations in the IGF-I and HPA axes. The findings may raise concern regarding maternal use of SSRIs during pregnancy.

DHEA lessens depressive-like behavior via GABA-ergic modulation of the mesolimbic system.

Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate gamma-aminobutyric-acid-type-A (GABA(A)R), N-methyl-D-aspartate (NMDAR), and Sigma-1 (sigma 1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether alterations in DHEA also occur in an animal model of depression, the Flinders-sensitive-line (FSL) rats, with the intention of determining the brain site of DHEA action and its antidepressant mechanism. We discovered that DHEA levels were lower in some brain regions involved with depression of FSL rats compared to Sprague-Dawley (SD) controls. Moreover, DHEA (1 mg/kg IP for 14 days)-treated FSL rats were more mobile in the forced swim test than FSL controls. In the NAc and VTA, significant changes were observed in the levels of the delta-subunit of GABA(A), but not of sigma 1R mRNA, in FSL rats compared to SD rats. The delta-subunit controls the sensitivity of the GABA(A)R to the neurosteroid. Indeed, treatment (14 days) of FSL rats with the GABA(A) agonist muscimol (0.5 mg/kg), together with DHEA (a negative modulator of GABA(A)), reversed the effect of DHEA on immobility in the swim test. Perfusion of DHEA sulfate (DHEAS) (3 nM and 30 nM for 14 days) into the VTA and NAc of FSL rats improved their performance in the swim test for at least 3 weeks post-treatment. Our results imply that alterations in DHEA are involved in the pathophysiology of depression and that the antidepressant action of DHEA is mediated via GABA(A)Rs in the NAc and VTA.

Improvement of aggressive behavior and quality of life impairment following S-adenosyl-methionine (SAM-e) augmentation in schizophrenia.

S-adenosyl-methionine (SAM-e), functions as a primary methyl group donor for several metabolic compounds. Since SAM-e is involved in several metabolic processes, its administration may have a role in the amelioration of several disorders. In addition, SAM-e increases catechol-O-methyltransferase (COMT) enzyme activity, which may ameliorate aggressive symptoms in certain patients. We have therefore investigated the efficacy of SAM-e in managing schizophrenia symptomatology in patients with the low activity COMT polymorphism. Eighteen patients with chronic schizophrenia were randomly assigned to receive either SAM-e (800 mg) or placebo for 8 weeks in double-blind fashion. Results indicated some reduction in aggressive behavior and improved quality of life following SAM-e administration. Female patients showed improvement of depressive symptoms. Clinical improvement did not correlate with serum SAM-e levels. Two patients receiving SAM-e exhibited some exacerbation of irritability. This preliminary pilot short-term study cautiously supports SAM-e as an adjunct in management of aggressive behavior and quality of life impairment in schizophrenia.

Neurosteroid blood levels in delinquent adolescent boys with conduct disorder.

Accumulating data indicates that neurosteroids can modulate aggressive behavior. The aim of the present study was to examine neurosteroid blood levels in delinquent adolescent boys as compared to normal healthy controls. Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S) and cortisol blood levels were measured in 16 delinquent adolescent (age 15.72+/-0.95 years) with conduct disorder (CD) and 11 normal controls (16.82+/-1.83 years). Severity of aggressive behavior was assessed by the Child Behavior Checklist (CBCL) and the Overt Aggression Scale (OAS). The delinquent adolescents tended to have higher DHEA-S levels than the normal control group (p=0.054). DHEA and cortisol levels did not differ between the two groups. The interaction between neurosteroids ( especial DHEA-S) and genetic, developmental and environmental factors in juvenile delinquency merits further investigation.

The effect of DHEA complementary treatment on heroin addicts participating in a rehabilitation program: a preliminary study.

We evaluated the effect of DHEA complementary treatment in opiate addicts undergoing detoxification. DHEA (100 mg/day) or placebo was added to the routine medication protocol in a randomized, double blind controlled study. Follow-up for 12 months was conducted. Two separate DHEA-treated subgroups were identified by the Fuzzy clustering method: one showed statistically significant improvement in the severity of withdrawal symptoms, depression and anxiety scores (n=34; p<0.001 for all) and the other subgroup deteriorated in all measures (n=15). DHEA at the end of the detoxification program showed a tendency towards correlation with the duration of abstinence (r=0.6843; p>0.05; n=6), while a negative correlation was obtained with the cortisol level (r=-0.900; p=0.005, n=8). The completion-rate of the DHEA-improved subgroup was greater than in the DHEA-deteriorated subgroup (64.7% vs. 33.3%, respectively). The influence of supplementary DHEA treatment was mostly effective in heroin addicts who had not previously used either cocaine or benzodiazepines and who had experienced only few withdrawal programs.