Add-on Pregnenolone with L-Theanine to Antipsychotic Therapy Relieves Negative and Anxiety Symptoms of Schizophrenia: An 8-week, randomized, double-blind, placebo-controlled trial (2015)

I haven’t yet seen the full text but here are the initial results from a trial I was keeping an eye on:

Add-on Pregnenolone with L-Theanine to Antipsychotic Therapy Relieves Negative and Anxiety Symptoms of Schizophrenia: An 8-week, randomized, double-blind, placebo-controlled trial (2015)

AIMS:

Pregnenolone (PREG) and L-Theanine (LT) have shown ameliorative effects on various schizophrenia symptoms. This is the first study to evaluate the efficacy and safety of augmentation of antipsychotic treatment among patients with chronic schizophrenia or schizoaffective disorder with PREG – LT.

METHODS:

Double-blind, placebo-controlled trial of PREG – LT or placebo augmentation was conducted for 8 weeks with 40 chronic DSM-IV schizophrenia and schizoaffective disorder patients with suboptimal response to antipsychotics. Oral PREG (50 mg/day) with LT (400 mg/day) or placebo were added to a stable regimen of antipsychotic medication from March 2011 to October 2013. The participants were rated using the Scale for the Assessment of Negative Symptoms (SANS), Hamilton Scale for Anxiety (HAM-A), and Positive and Negative Syndrome Scale (PANSS) scales bi-weekly. The decrease of SANS and HAM-A scores were the co-primary outcomes. Secondary outcomes included assessments of general functioning and side effects.

RESULTS:

Negative symptoms such as blunted affect, alogia, and anhedonia (SANS) were found to be significantly improved, with moderate effect sizes among patients who received PREG-LT, in comparison with the placebo group. Add-on PREG-LT also significantly associated with a reduction of anxiety scores such as anxious mood, tension, and cardiovascular symptoms (HAM-A), and elevation of general functioning (GAF). Positive symptoms, antipsychotic agents, concomitant drugs, and illness duration did not associate significantly with effect of PREG-LT augmentation. PREG-LT was well-tolerated.

CONCLUSIONS:

Pregnenolone with L-Theanine augmentation may offer a new therapeutic strategy for treatment of negative and anxiety symptoms in schizophrenia and schizoaffective disorder. Further studies are warranted.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01831986.


See also:

Effect of l-theanine on glutamatergic function in patients with schizophrenia (2015)

Neurosteroids as therapeutics

Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review (2015)

Dietary and nutritional therapies for schizophrenia

Clinical Management of Negative Symptoms of Schizophrenia: An update (2015)

My trials with supplements for schizophrenia

Targeting neurosteroid synthesis as a therapy for schizophrenia-related alterations induced by early psychosocial stress (2015)

Expanding on Neurosteroids as therapeutics:

Targeting neurosteroid synthesis as a therapy for schizophrenia-related alterations induced by early psychosocial stress

Background

Cogent evidence has shown that schizophrenia vulnerability is enhanced by psychosocial stress in adolescence, yet the underpinnings of this phenomenon remain elusive. One of the animal models that best capture the relationship between juvenile stress and schizophrenia is isolation rearing (IR). This manipulation, which consists in subjecting rats to social isolation from weaning through adulthood, results in neurobehavioral alterations akin to those observed in schizophrenia patients. In particular, IR-subjected rats display a marked reduction of the prepulse inhibition (PPI) of the startle reflex, which are posited to reflect imbalances in dopamine neurotransmission in the nucleus accumbens (NAcc). We recently documented that the key neurosteroidogenic enzyme 5α-reductase (5αR) plays an important role in the dopaminergic regulation of PPI; given that IR leads to a marked down-regulation of this enzyme in the NAcc, the present study was designed to further elucidate the functional role of 5αR in the regulation of PPI of IR-subjected rats.

Methods

We studied the impact of the prototypical 5αR inhibitor finasteride (FIN) on the PPI deficits and NAcc steroid profile of IR-subjected male rats, in comparison with socially reared (SR) controls.
Results

FIN (25–100 mg/kg, i.p.) dose-dependently countered IR-induced PPI reduction, without affecting gating integrity in SR rats. The NAcc and striatum of IR-subjected rats displayed several changes in neuroactive steroid profile, including a reduction in pregnenolone in both SR and IR-subjected groups, as well as a decrease in allopregnanolone content in the latter group; both effects were significantly opposed by FIN.

Conclusions

These results show that 5αR inhibition counters the PPI deficits induced by IR, possibly through limbic changes in pregnenolone and/or allopregnanolone concentrations.


  • Isolation rearing (IR) leads to significant reductions in pregnenolone, 5α-dihydroprogesterone, allopregnanolone and estradiol in the NAcc, but no significant changes in progesterone, DHEA or testosterone levels
  • the potent 5αR inhibitor finasteride (FIN) dose-dependently countered the deficits in PPI caused by isolation rearing
  • the effects of FIN were generally similar to those of  haloperidol; however, the 5αR blocker failed to induce catalepsy or other overt extrapyramidal manifestations.
  • while FIN reduced allopregnanolone levels and allopregnanolone/5α-dihydroprogesterone ratio in socially reared (SR) rats, this drug had surprisingly opposite effects in IR-subjected rats: enhancement of allopregnanolone synthesis in isolation reared rats may play a key contributory role in the effects of FIN (via GABA-A mediated effects).
    • functional changes in 3α-hydroxysteroid oxido-reductase (3α-HSOR), the reversible enzyme involved in the inter-conversion of allopregnanolone and 5α-dihydroprogesterone may be involved in allopregnanolone elevations
    • down-regulation of 5αR in IR rats may unmask other secondary mechanisms of FIN, such as the inhibition of 5β-reductase, which may paradoxically enhance the synthesis of allopregnanolone and other 5α-reduced neurosteroids.
  • Previous observations revealed ameliorative effects of FIN and other 5αR inhibitors on psychosis-related alterations elicited by direct and indirect DAergic agonists in rodents
  • On the contrary, a different study found that finasteride administration potentiates the disruption of prepulse inhibition induced by forced swim stress [1]

“… the effects of FIN on the regulation of PPI are likely supported by changes in the signaling of the postsynaptic DA receptors in the NAcc (Devoto et al., 2012). Furthermore, several studies have shown that the gating deficits induced by IR are primarily mediated by this region (Powell et al., 2003 and Leng et al., 2004). Our results showed that IR leads to significant reductions in pregnenolone, 5α-dihydroprogesterone, allopregnanolone and estradiol in the NAcc. These data are in substantial agreement with previous findings from our group and others, indicating that IR leads to an overall reduction in steroid levels in the cortex (Serra et al., 2000 and Bortolato et al., 2011). We also documented no significant changes in progesterone, DHEA and testosterone levels, suggesting that the generalized reduction in neurosteroid biosynthetic pathways may be partially offset by the down-regulation of catabolic enzymes and/or the activation of alternative anabolic processes. The significant changes in steroid ratios are in keeping with the previously documented down-regulation of 5αR in IR-subjected rats (as indicated by the reduction in 5α-dihydroprogesterone/progesterone ratio); furthermore, our data suggest that this manipulation may lead to functional alterations of other neurosteroidogenic enzymes, such as a potential enhancement of the activity of 3β-hydroxysteroid dehydrogenase (3β-HSD), which catalyze the conversion of pregnenolone into progesterone”

“[the effects of] FIN were paralleled by a marked increase in the concentrations of pregnenolone and a statistical trend for an enhancement of DHEA levels in the NAcc and striatum. The increased content of these 3β-hydroxy-Δ5-steroids may signify their accumulation in response to the inhibition of 5αR, given that they are the precursors of the two main 5αR substrates, i.e., progesterone and testosterone. The possibility that the antipsychotic-like actions of FIN may be contributed by the enhancement of pregnenolone (and, possibly, DHEA) levels is in keeping with emerging evidence supporting the therapeutic potential of these neurosteroids for cognitive and negative symptoms in schizophrenia”

Synoptic schematization of the observed effects of isolation rearing (IR) and finasteride (FIN) on neurosteroid levels in the nucleus accumbens (NAcc). Black and white arrows represent increased and decreased enzyme activities, respectively. CYP17A1, 17-hydroxylase/17,20 lyase; 3β-HSD, 3β-hydroxysteroid dehydrogenase; 5αR, 5α-reductase; 3α-HSOR, 3α-hydroxysteroid oxidoreductase; DHEA, dehydroepiandrosterone
Synoptic schematization of the observed effects of isolation rearing (IR) and finasteride (FIN) on neurosteroid levels in the nucleus accumbens (NAcc). Black and white arrows represent increased and decreased enzyme activities, respectively. CYP17A1, 17-hydroxylase/17,20 lyase; 3β-HSD, 3β-hydroxysteroid dehydrogenase; 5αR, 5α-reductase; 3α-HSOR, 3α-hydroxysteroid oxidoreductase; DHEA, dehydroepiandrosterone

“…our findings have confirmed FIN’s antipsychotic-like properties, by documenting its ability to correct the gating alterations associated with IR, a neurodevelopmental model of schizophrenia with high face, construct and predictive validity. The actions of FIN are accompanied by changes in neuroactive steroid levels, such as an increase in pregnenolone and allopregnanolone, which countered the effects of IR. These data further confirm previous evidence pointing to 5αR as a promising target for the development of novel treatments for schizophrenia and other neuropsychiatric disorders featuring stress-related gating impairments, such as Tourette syndrome and obsessive–compulsive disorder.”

Neurosteroids as therapeutics

Pregnenolone is a promising therapeutic option for schizophrenia and has briefly been discussed earlier. The administration of pregnenolone (PREG) increases CNS PREG and its sulfate (PregS) concentrations, along with those of 5α-reduced neurosteroids such as allopregnanolone.

https://i2.wp.com/www.neurology.org/content/68/12/945/F1.large.jpg

“Neurosteroids perform a variety of actions that impact critical brain functions such as modulation of inhibitory GABAergic and excitatory glutamatergic neurotransmitter systems, myelination, reduction of apoptosis, and reduction of inflammatory responses. Pregnenolone and its metabolite pregnenolone sulfate, belong to the group of neurosteroids found in high concentrations in certain areas in the brain which positively modulate excitatory glutamatergic NMDA receptors.

Pregnenolone administration results in elevations in downstream neurosteroids, such as allopregnanolone, a molecule with neuroprotective effects that also increases neurogenesis, decreases apoptosis and inflammation (thus its downstream anti-inflammatory function), modulates the hypothalamic-pituitary-adrenal axis, and markedly increases GABA (A) receptor responses. Pregnenolone and its sulfate ester are under investigation for their potential to improve cognitive and memory functioning.

Emerging preclinical and clinical evidence suggests pregnenolone may be a promising novel therapeutic candidate in schizophrenia.” [review]

From “Contribution of sex hormones to gender differences in schizophrenia: A review“:

  • Estrogen modulates the release of several monoamines, including serotonin, norepinephrine, dopamine and glutamate, and also enhances acetylcholine levels and inhibits gamma-aminobutyric acid (GABA) receptors. Its effect on these neurotransmitter systems has been likened to that of atypical antipsychotics, and may contribute to the lower illness severity and better outcomes in female patients.
  • Progesterone is also thought to play a role in serotonin, norepinephrine, dopamine and glutamate modulation. In addition, it has also been found to inhibit GABA receptors. These actions contribute to positive effects on cognition, sensorimotor performance and other aspects of neuropsychiatric illnesses, suggesting possible ways in which progesterone may beneficially affect symptomatology in female patients.
  • Testosterone has been shown to inhibit reuptake of both serotonin and norepinephrine, but to a significantly lesser degree than antidepressants. It also enhances glutamate release, and of particular relevance to schizophrenia, dopamine release, possibly contributing to increased negative symptoms and psychosis, and leading to greater illness severity in males.
  • DHEA moderates glutamate receptor activity, while DHEAS increases glutamate, acetylcholine and norepinephrine release. Both, but particularly DHEAS , are also GABA receptor antagonists. This neurotransmitter modulatory profile, which is more similar to that of estrogen, though not as broad-ranging, could have a more favorable impact on symptomatology.

Recently, 5α-reduced neurosteroids have been found to sex-dependently reverse central prenatal programming of neuroendocrine stress responses, including hyperactivity of the HPA axis [1]

Pregnenolone and its metabolites have beneficial effects in relation to schizophrenia:

A Role for Picomolar Concentrations of Pregnenolone Sulfate in Synaptic Activity-dependent Ca2+ signaling and CREB Activation.

Pregnenolone rescues schizophrenia-like behavior in dopamine transporter knockout mice.

Pregnenolone can also act as a signaling-specific inhibitor of the CB1 receptor [2]. Pregnenolone sulfate blocks NMDA antagonist-induced deficits in animals (acting as a positive allosteric modulator at the NMDA receptor), modulates activity of other neurotransmitter receptors and ion channels, including AMPA, kainate, [3, 4] and GABAA receptors [5], as well as certain voltage-gated calcium channels [6]. Nanomolar concentrations of pregnenolone sulfate are able to increase DA overflow in the striatum through an NMDA receptor mediated pathway [7]

Table 2: Neurotransmitter receptors affected by neurosteroids<sup>[7]</sup>Biosynthesis, mechanism of action, and clinical importance of neuroactive steroids: Pearls from literature


There are both short-term adaptive actions in neurosteroid regulation of the HPA axis (allostasis) that are protective, and long-term effects that can be damaging:

3α,5α-reduced metabolites of progesterone (P) and deoxycorticosterone, allopregnanolone (ALLO) and allotetrahydrodeoxycorticosterone (ALLO-THDOC), respectively, represent allostatic mechanisms in the context of adaptation to stress by limiting the extent and duration of reduction of gamma-aminobutyric acid (GABA)ergic inhibitory transmission and activation of the HPA axis.

– P and ALLO are both stress-responsive (i.e., they increase during stress) and stress-reducing (they down-regulate stress and anxiety). Social stress induced significant increases in progesterone in healthy subjects
– Stress-induced P (and ALLO) increases may partly function to promote affiliation as a stress-coping strategy and there appears to be a relationship between P and motivation to affiliate, perhaps particularly in the context of rejection or exclusion
– 5α-reductase, the rate-limiting enzyme in the conversion of progesterone to ALLO, is downregulated following chronic social isolation.
– Inhibition of 5α-reductase with finasteride potentiates the disruption of prepulse inhibition induced by forced swim stress [link]
– the synthesis of ALLO and ALLO-THDOC may be diminished in the context of chronic stress. The observed reductions in endogenous brain and plasma ALLO concentrations in socially isolated rats has been associated with reduced feedback sensitivity of the HPA axis to dexamethasone (DEX) challenge
– ALLO administration down-regulates gene transcription for the HPA axis hormones corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP)
– ALLO and other GABA-A modulators exert bimodal/paradoxical effects, both in humans and laboratory animals: low doses have been found to increase negative mood and anxiety-like behaviors, whereas high doses reduce anxiety.

https://i1.wp.com/www.frontiersin.org/files/Articles/11799/fendo-02-00019-HTML/image_m/fendo-02-00019-g003.jpg
Neural, genetic, and behavioral effects of progesterone (P) and allopregnanolone (ALLO).

The pharmacology of allopregnanolone is discussed in the following articles:

Beyond the HPA Axis: Progesterone-Derived Neuroactive Steroids in Human Stress and Emotion.

GABAA receptor-acting neurosteroids: A role in the development and regulation of the stress response.

The reciprocal regulation of stress hormones and GABA(A) receptors.

Effects and Mechanisms of 3α,5α,-THP on Emotion, Motivation, and Reward Functions Involving Pregnane Xenobiotic Receptor.

⇒ Approaches to increase allopregnanolone levels are TSPO modulators or low dose SSRIs .

Enhancing Neurosteroid Synthesis – Relationship to the Pharmacology of Translocator Protein (18kDa) (TSPO) Ligands and Benzodiazepines.

Anxiety disorders and GABA neurotransmission: a disturbance of modulation


DHEA (also via its sulfate, see figure 1, 2) shows anti-glucocorticoid, pro-neurogenic [including TrkA agonism], neuroprotective [including via ERα and ERβ-mediated effects], sigma-1 receptor agonism, NMDAR enhancing, catecholaminergic, antioxidant, anti-inflammatory and immunomodulating activity amongst other promising activities, similarly implicating it as a potential therapy for negative, depressive and anxiety symptoms in schizophrenia

“Dehydroepiandrosterone (DHEA), an androgenic hormone and precursor to androstenedione, along with its sulfate ester DHEA-S, which together comprise the most abundant steroid hormone(s) in the human body, are associated with GABAA receptor (GABAAR) interactions and also exert profound antiglucocorticoid effects. Current evidence suggests that the antiglucocorticoid effects of DHEA, or its metabolites, on cortisol may involve inhibition of the intermediary enzymes involved in the conversion of the inactive cortisol metabolite, cortisone, to cortisol. In this way, DHEA may represent additional neurosteroid mechanisms in humans that are of relevance to the regulation of the HPA axis response to stress.

– DHEA is stress responsive, and is co-released with cortisol via ACTH stimulation of adrenal DHEA synthesis.
Research has demonstrated positive modulation of the HPA axis by DHEA and DHEA sulfate, which could be explained by their actions as negative allosteric modulators of GABAA receptors and positive allosteric modulators of NMDA receptors, alongside their interactions with sigma-1 receptors.
– DHEA appears to influence the release of other GABAergic neurosteroids which are positive modulators of the GABAAR, leading to additional modulation of the HPA axis
– Acute psychosocial stress has also been shown to substantially increase DHEA and DHEA-S concentrations in humans (by as much as 60–75 % above baseline concentrations).  On the contrary, the majority of studies suggest reduced basal levels of DHEA or DHEA-S in association with chronic psychosocial stress
DHEA add-on therapy improves mood, decision making and reduces subsequent relapse in polydrug users, with the level of DHEA-S predicting the likelihood of relapse

“Diminished neurosteroid availability may impair the normal negative feedback regulation of the HPA axis, and thus contribute to elevated HPA axis activation. Since stress-induced increases in ACTH are involved in the biosynthesis of neurosteroids of adrenal origin, chronic HPA axis activation could contribute to reduced ALLO and ALLOTHDOC in socially isolated animals via a chronic “wear and tear” on adrenal functioning, eventually leading to a state of adrenal “exhaustion” and reduced neurosteroid synthesis—a prototypical expression of allostatic load.

In humans, initial HPA axis hyperactivity associated with stress is reduced in response to prolonged chronic stress exposure, and may even manifest as blunted HPA axis activation over time. Additionally, higher tonic activation of the HPA axis following chronic stress may lead to blunted cortisol reactions to acute stress, due to a “ceiling effect,” and thereby inhibit the potential for appropriate HPA axis stress reactivity.”


“The role of stress in the development and exacerbation of psychosis in schizophrenia has been demonstrated. Abnormal dopaminergic activity has been well documented in schizophrenia. There is enough evidence showing a deficit of GABAergic and glutamatergic activity in schizophrenia. Neuroactive steroids, as we know, modulate the activity of all of these systems, both directly and indirectly, therefore contributing to the pathophysiology of the illness. Hence, they may play a role in the therapeutic benefi ts of antipsychotic drugs, particularly those whose actions involve the GABA A receptor complex.

Studies have reported low DHEA levels in the morning in chronically ill unmedicated patients with schizophrenia, compared with healthy control subjects. However, a recent study reported elevated DHEA plasma levels and, interestingly, DHEA levels correlated inversely with the severity of negative symptoms in drug-free men with first-episode psychosis. There have also been reports of elevated plasma DHEAS levels in medicated young men with psychosis, as well as of low estradiol and high testosterone but unchanged DHEAS plasma levels in medicated young women with psychosis, when compared with healthy control subjects. Studies have found cortisol levels to be directly and testosterone levels to be inversely correlated with the severity of negative symptoms in patients with schizophrenia. It was further supported by studies involving measurement of cortisol-to-DHEA and cortisol-to-DHEAS ratios in patients with schizophrenia, which were significantly higher than those in healthy control subjects, although the ratios did not correlate with the severity of symptoms of schizophrenia.

Abnormal serum levels of progesterone have also been reported in some patients with schizophrenia.  It may be possible that progesterone acts like an endogenous antipsychotic and anxiolytic and that an increase in progesterone levels during the early phase of the illness and during times of stress serves to restore normal functioning. Steroid levels in patients with schizophrenia, compared with control subjects are shown in the table

To our surprise, it has been found that concentrations of neuroactive steroids may be affected by antipsychotic treatment. Atypical, but not typical, antipsychotics have been found to alter brain levels of neurosteroids.The atypical agents like olanzapine and clozapine increase concentrations of cortical 3α,5α-THP and progesterone dose dependently, and clozapine increases concentrations of cortical 3α,5α-THDOC following acute administration in rats. Antipsychotic-induced alterations in neurosteroid levels may contribute to the antipsychotic effects of these drugs.

Reduced GABAergic neurotransmission may contribute to the pathophysiology of schizophrenia. Thus, antipsychotic-induced increase of 3α,5α-THP, a positive allosteric modulator of GABA A receptors, and decrease of DHEA and DHEAS, negative allosteric modulators of GABA A receptors, may augment GABAergic tone in the cortex, resulting in improvement in symptoms.”

Table 3: Steroid levels in patients with schizophrenia, compared with control subjects<sup>[18]</sup>
Steroid levels in patients with schizophrenia, compared with control subjects

There are several studies involving augmentation with pregnenolone (50-500mg/day) in schizophrenia. A proof-of-concept trial evaluating adjunctive therapy with pregnenolone at 500 mg/day demonstrated significantly greater improvement in negative symptoms. Other subsequent, small studies also supported the benefit of pregnenolone in schizophrenia:

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.

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 treatment reduces severity of negative symptoms in recent-onset schizophrenia: an 8-week, double-blind, randomized add-on two-center trial.

Management of recent-onset schizophrenia (SZ) and schizoaffective disorder (SA) is challenging owing to frequent insufficient response to antipsychotic agents. This study aimed to test the efficacy and safety of the neurosteroid pregnenolone in patients with recent-onset SZ/SA. Sixty out- and inpatients who met DSM-IV criteria for SZ/SA, with suboptimal response to antipsychotics were recruited for an 8-week, double-blind, randomized, placebo-controlled, two-center add-on trial, that was conducted between 2008 and 2011. Participants were randomized to receive either pregnenolone (50 mg/day) or placebo added on to antipsychotic medications. The primary outcome measures were the Positive and Negative Symptoms Scale and the Assessment of Negative Symptoms scores. Secondary outcomes included assessments of functioning, and side-effects. Analysis was by linear mixed model. Fifty-two participants (86.7%) completed the trial. Compared to placebo, adjunctive pregnenolone significantly reduced Positive and Negative Symptoms Scale negative symptom scores with moderate effect sizes (d = 0.79). Significant improvement was observed in weeks 6 and 8 of pregnenolone therapy among patients who were not treated with concomitant mood stabilizers (arms × visit × mood stabilizers; P = 0.010). Likewise, pregnenolone significantly reduced Assessment of Negative Symptoms scores compared to placebo (d = 0.57), especially on blunted affect, avolition and anhedonia domain scores. Other symptoms, functioning, and side-effects were not significantly affected by adjunctive pregnenolone. Antipsychotic agents, benzodiazepines and sex did not associate with pregnenolone augmentation. Pregnenolone was well tolerated. Thus, add-on pregnenolone reduces the severity of negative symptoms in recent-onset schizophrenia and schizoaffective disorder, especially among patients who are not treated with concomitant mood stabilizers. Further studies are warranted.

Adjunctive pregnenolone ameliorates the cognitive deficits in recent-onset schizophrenia.

This study aimed to examine the effect of add-on treatment with the neurosteroid pregnenolone (PREG) on neurocognitive dysfunctions of patients with recent-onset schizophrenia (SZ) and schizoaffective disorder (SA). Sixty out-and inpatients that met DSM-IV criteria for SZ/SA were randomized an 8-week, double-blind, randomized, placebo-controlled, 2-center trial. Participants received either pregnenolone (50 mg/d) or placebo added on to antipsychotic medications. Computerized Cambridge Automated Neuropsychological Test Battery measures were administered at baseline and after 4 and 8 weeks of treatment. ANOVA and paired t or z-tests were applied to examine between- and within-group differences over time.RESULTS: Compared to placebo, adjunctive PREG significantly reduced the deficits in visual attention measured with the Matching to Sample Visual Search task (p=0.002) with moderate effect sizes (d= 0.42). In addition, a significant improvement was observed from baseline to end-of-study with respect to the visual (p= 0.008) and sustained attention (Rapid Visual Information Processing, p=0.038) deficits, and executive functions (Stockings of Cambridge, p=0.049; Spatial Working Memory, p<0.001) among patients receiving PREG, but not among those receiving placebo (all p’s >0.05). This beneficial effect of PREG was independent of the type of the antipsychotic agents, gender, age, education, and illness duration.CONCLUSIONS: Pregnenolone augmentation demonstrated significant amelioration of the visual attention deficit in recent-onset SZ/SA. Long-term, large-scale studies are required to obtain greater statistical significance and more confident clinical generalization.

A clinical trial of a combination of pregnenolone (50mg/day) and L-theanine (400mg/day) is currently recruiting:

Pregnenolone and L-theanine Augmentation in the Treatment for Schizophrenia and Schizoaffective Disorders

“Schizophrenia (SZ) and schizoaffective (SA) disorders are comprised of several debilitating symptoms. It was suggested that compounds with neuroprotective effects might be useful in the management of SZ/SA symptoms. Our previous clinical trials indicated significant beneficial effects for augmentations with two different neuroprotective agents: Pregnenolone and L-Theanine. Pregnenolone (PREG) is a neurosteroid, which displays multiple effects on the central nervous system. Our recent 8-week, randomized, double-blind trial among patients with chronic SZ/SA disorders, in which PREG versus placebo and DHEA was added to antipsychotics, yielded encouraging results: PREG augmentation demonstrated significant amelioration of positive symptoms, EPS, as well as an improvement in attention, and working memory performance of SZ/SA disorder patients (Ritsner et al 2010). L-Theanine is a unique amino acid present almost exclusively in the tea plant. It possesses neuroprotective, mood-enhancing, and relaxation activities. L-theanine augmentation to antipsychotic therapy can ameliorate positive, activation, and anxiety symptoms in SZ/SA disorder patients (grant # 06TGF-911, (Ritsner et al 2010). This proposed study would extend our prior research with Pregnenolone and L-theanine by combining both agents versus placebo. We hypothesized that addition of both these compounds to ongoing antipsychotics would significantly improve the clinical status of SZ/SA patients.

Methods: In an 8-week, randomized, double-blind placebo-controlled trial a combination of PREG (50 mg/day) with L-theanine (400 mg/day) versus placebo will be added to the stable ongoing antipsychotic treatment of 200 patients with schizophrenia or schizoaffective disorders. This trial will be conducted at five sites in Israel. Participants will be assessed at baseline and after 2, 4, 6 and 8 weeks of treatment. A battery of research instruments will be used for the assessment of psychopathology, side effects, general functioning and quality of life”


Interestingly, fMRI studies of acute pregnenolone and DHEA administration have revealed some enhancements of emotion regulation and anxiety-related neurocircuitry in healthy humans:

Allopregnanolone Elevations Following Pregnenolone Administration Are Associated with Enhanced Activation of Emotion Regulation Neurocircuits.

BACKGROUND: The neurosteroid allopregnanolone is a potent allosteric modulator of the gamma-aminobutyric acid type A receptor with anxiolytic properties. Exogenous administration of allopregnanolone reduces anxiety, and allopregnanolone blockade impairs social and affective functioning. However, the neural mechanism whereby allopregnanolone improves mood and reduces anxiety is unknown. In particular, brain imaging has not been used to link neurosteroid effects to emotion regulation neurocircuitry. METHODS: To investigate the brain basis of allopregnanolone’s impact on emotion regulation, participants were administered 400 mg of pregnenolone (n=16) or placebo (n=15) and underwent 3T functional magnetic resonance imaging while performing the shifted-attention emotion appraisal task, which probes emotional processing and regulation. RESULTS:  Compared with placebo, allopregnanolone was associated with reduced activity in the amygdala and insula across all conditions. During the appraisal condition, allopregnanolone increased activity in the dorsal medial prefrontal cortex and enhanced connectivity between the amygdala and dorsal medial prefrontal cortex, an effect that was associated with reduced self-reported anxiety. CONCLUSIONS: These results demonstrate that in response to emotional stimuli, allopregnanolone reduces activity in regions associated with generation of negative emotion. Furthermore, allopregnanolone may enhance activity in regions linked to regulatory processes. Aberrant activity in these regions has been linked to anxiety psychopathology. These results thus provide initial neuroimaging evidence that allopregnanolone may be a target for pharmacologic intervention in the treatment of anxiety disorders and suggest potential future directions for research into neurosteroid effects on emotion regulation neurocircuitry

The neurosteroids allopregnanolone and dehydroepiandrosterone modulate resting-state amygdala connectivity.

The neurosteroids allopregnanolone and dehydroepiandrosterone (DHEA) are integral components of the stress response and exert positive modulatory effects on emotion in both human and animal studies. Although these antidepressant and anxiolytic effects have been well established, to date, little research has examined their neural correlates, and no research has been conducted into the effects of neurosteroids on large-scale networks at rest. To investigate the neurosteroid impact on intrinsic connectivity networks, participants were administered 400 mg of pregnenolone (N=16), 400 mg of DHEA (N=14), or placebo (N=15) and underwent 3T fMRI. Resting-state brain connectivity was measured using amygdala as a seed region. When compared with placebo, pregnenolone administration reduced connectivity between amygdala and dorsal medial prefrontal cortex, between amygdala and precuneus, and between amygdala and hippocampus. DHEA reduced connectivity between amygdala and periamygdala and between amygdala and insula. Reductions in amygdala to precuneus connectivity were associated with less self-reported negative affect. These results demonstrate that neurosteroids modulate amygdala functional connectivity during resting state and may be a target for pharmacological intervention. Additionally, allopregnanolone and DHEA may shift the balance between salience network and default network, a finding that could provide insight into the neurocircuitry of anxiety psychopathology.

DHEA enhances emotion regulation neurocircuits and modulates memory for emotional stimuli.

Dehydroepiandrosterone (DHEA) is a neurosteroid with anxiolytic, antidepressant, and antiglucocorticoid properties. It is endogenously released in response to stress, and may reduce negative affect when administered exogenously. Although there have been multiple reports of DHEA’s antidepressant and anxiolytic effects, no research to date has examined the neural pathways involved. In particular, brain imaging has not been used to link neurosteroid effects to emotion neurocircuitry. To investigate the brain basis of DHEA’s impact on emotion modulation, patients were administered 400 mg of DHEA (N=14) or placebo (N=15) and underwent 3T fMRI while performing the shifted-attention emotion appraisal task (SEAT), a test of emotional processing and regulation. Compared with placebo, DHEA reduced activity in the amygdala and hippocampus, enhanced connectivity between the amygdala and hippocampus, and enhanced activity in the rACC. These activation changes were associated with reduced negative affect. DHEA reduced memory accuracy for emotional stimuli, and also reduced activity in regions associated with conjunctive memory encoding. These results demonstrate that DHEA reduces activity in regions associated with generation of negative emotion and enhances activity in regions linked to regulatory processes. Considering that activity in these regions is altered in mood and anxiety disorders, our results provide initial neuroimaging evidence that DHEA may be useful as a pharmacological intervention for these conditions and invite further investigation into the brain basis of neurosteroid emotion regulatory effects.


Pregnenolone has also shown promise in bipolar depression, with doses titrated up to 500mg/day.

A Randomized, Double-Blind, Placebo-Controlled Trial of Pregnenolone for Bipolar Depression

Depression in bipolar disorder (BPD) is challenging to treat. Therefore, additional medication options are needed. In the current report, the effect of the neurosteroid pregnenolone on depressive symptoms in BPD was examined. Adults (n=80) with BPD, depressed mood state, were randomized to pregnenolone (titrated to 500 mg/day) or placebo, as add-on therapy, for 12 weeks. Outcome measures included the 17-item Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology—Self-Report (IDS-SR), Hamilton Rating Scale for Anxiety (HRSA), and Young Mania Rating Scale (YMRS). Serum neurosteroid levels were assessed at baseline and week 12. Data were analyzed using a mixed model ANCOVA with a between factor of treatment assignment, a within factor (repeated) of visit, and the baseline value, as well as age and gender, as covariates. In participants with at least one postbaseline visit (n=73), a significant treatment by week interaction for the HRSD (F(5,288)=2.61, p=0.025), but not IDS-SR, was observed. Depression remission rates were greater in the pregnenolone group (61%) compared with the placebo group (37%), as assessed by the IDS-SR (χ2(1)=3.99, p=0.046), but not the HRSD. Large baseline-to-exit changes in neurosteroid levels were observed in the pregnenolone group but not in the placebo group. In the pregnenolone group, baseline-to-exit change in the HRSA correlated negatively with changes in allopregnanolone (r(22)=−0.43, p=0.036) and pregNANolone (r(22)=−0.48, p=0.019) levels. Pregnenolone was well tolerated. The results suggest that pregnenolone may improve depressive symptoms in patients with BPD and can be safely administered.


See also:

Targeting neurosteroid synthesis as a therapy for schizophrenia-related alterations induced by early psychosocial stress (2015)