Although antipsychotics have proven effective in ameliorating psychotic symptoms, in a substantial proportion of recent-onset schizophrenia (SZ) and schizoaffective (SA) disorder patients, the clinical response remains insufficient. When response to antipsychotics is inadequate, augmentation strategies are often implemented.
Pregnenolone (PREG), pregnenolone sulfate (PREGS), dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS), progesterone and androstenedione are called ‘neuroactive steroids’ and ‘neurosteroids’ as they are produced in situ in the brain, adrenal glands and gonads. PREG and other neurosteroids act as potential signaling molecules for neocortical organization during brain development and regulate neuronal function by affecting neuronal excitability through prominent modulatory effects on the γ-aminobutyric acid type A (GABAA), N-methyl-D-aspartate (NMDA), sigma-1,[1, 2] cholinergic and dopamine systems. They regulate the growth of neurons and cerebral brain-derived neurotrophic factor levels, enhance myelination and synaptogenesis, and exhibit neuroprotective properties.
There is evidence that PREG and its metabolites may be involved in the pathophysiology of schizophrenia, mood disorders, dementia and substance abuse.[6-8] Clinical studies demonstrated low circulating levels of PREG in the elderly, including those with dementia, in individuals with major depression, anxiety disorder, and in chronic medicated schizophrenia patients.
Two clinical trials with add-on PREG in chronic SZ/SA were published. Marx et al. claimed that nine patients receiving PREG (fixed escalating doses to 500 mg/day) added on to second-generation antipsychotics (SGA) demonstrated significantly (P = 0.048) greater improvement in the Scale for the Assessment of Negative Symptoms (SANS) scores compared with nine patients who received placebo. This pilot study was based on an extremely small sample and had other limitations.
Another study investigated adjunctive ‘low-dose’ and ‘high-dose’ PREG (30 mg/day and 200 mg/day, respectively) added to ongoing antipsychotics in the treatment of chronic SZ/SA in an 8-week, controlled, double-blind, randomized, parallel-group trial. Fifty-eight patients were randomized, 44 patients completed the trial. Compared with placebo, PREG-30 administration was associated with significant reduction in positive symptom scores, extrapyramidal symptoms, improvement in attention, and working memory performance, whereas subjects treated with PREG-200 did not differ on outcome variable scores. PREG was well tolerated. Circulating PREG was found to be significantly higher among the patients treated by PREG compared to the placebo group. More detailed reviews of PREG's metabolism, mode of action, and these pilot trials were recently published.[12, 14]
We conducted a randomized, double-blind, placebo-controlled study among a sample of 60 patients with recent-onset SZ/SA. Add-on PREG (50 mg/day) for 8 weeks demonstrated significant amelioration of the visual attention deficit measured with the Matching to Sample Visual Search task compared to the placebo group in recent-onset SZ/SA. This report aimed to test the efficacy and safety of the neurosteroid PREG in patients with DSM-IV recent-onset SZ/SA. We hypothesized that add-on PREG compared to placebo would diminish persistent clinical symptoms in patients with recent-onset psychotic disorders.
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Table 3 presents analysis of interaction between the reduction in the PANSS negative scale scores and the patient's treatment with mood stabilizers (arms × time × mood stabilizers; F = 3.35, P = 0.010). For 14 patients of both groups who received mood stabilizers there was no significant difference between the two treatment arms, however there was significant improvement in the PREG group compared to the placebo group that was not concomitantly treated with mood stabilizers.
Table 3. Mixed model estimates of PANSS negative scale scores and effects of the concomitant treatment with mood stabilizers
|Effect||d.f.||Den d.f.||F value||Pr > F|
|Arms (pregnenolone vs placebo)||1||62.45||3.20||0.078|
|Time (visit: week 0, 2, 4, 6, and 8)||4||196.3||19.57||<0.0001|
|Treatment arms × Time (visit)||4||196.4||1.31||0.267|
|Treatment arms × Mood stabilizers||1||168.7||2.73||0.100|
|Time × Mood stabilizers||4||196.4||3.31||0.011|
|Treatment arms × Time × Mood stabilizers||4||196.4||3.35||0.010|
|Adjustment for Multiplicity: Simulated|
|Treatment arms||Time (week)a||Estimate||Error||d.f.||t-value||Pr > |t|||Adj P|
|Patients not treated with mood stabilizers|
|Pregnenolone versus placebo||2||−1.16||1.30||198.5||−0.89||0.373||0.950|
|Patients treated with mood stabilizers|
|Pregnenolone versus placebo||2||1.36||0.76||198.8||1.81||0.072||0.382|
Accordingly, the change versus baseline in weeks 6 and 8 was different between arms for patients not treated with mood stabilizers (P = 0.005, adj. P = 0.038, and P = 0.008, adj. P = 0.050, respectively). No significant main effect of the DSM-IV diagnosis, sex, concomitant treatment with benzodiazepines, and anti-Parkinson agents, type of antipsychotics, and interactions, such as arms by type of antipsychotics and by visits on PANSS subscales, SANS, GAF, and ESRS ratings, was observed (all P-values > 0.05).
Tolerability and safety
Before starting this trial, 17 patients in the PREG group and 16 patients in the placebo group were treated with anti-Parkinson agents. One patient (treated with haloperidol decanoate and PREG) was dropped from the study because of an extrapyramidal adverse event. No other new treatment-related adverse events occurred in either group. No differences between the two treatment arms were noted on ESRS scores (F1,260 = 0.66, P = 0.42). Both PREG and placebo augmentation resulted in statistically significant decreases from baseline to end-point of the study on the ESRS (F4,260 = 15.1, P < 0.001), without significant interaction: treatment arms × time (F4,260 = 0.64, P = 0.63). There were no clinically significant changes in vital signs, electrocardiograms, or clinical laboratory variables associated with treatment. Thus, the administration of PREG was well tolerated.
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This is the first randomized, double-blind, placebo-controlled add-on trial of PREG 50 mg/day to ongoing antipsychotic treatment in subjects suffering from recent-onset SZ/SA with suboptimal response to antipsychotics. Several comments and possible explanations for the obtained findings need to be considered.
First, add-on PREG 50 mg/day for 8 weeks significantly reduced PANSS negative scale and SANS total scores in comparison to placebo with moderate effect sizes (Cohen d = 0.79 and d = 0.57, respectively). The responding symptoms included PANSS emotional and apathetic social withdrawal, poor rapport, and stereotyped thinking (N2, N3, N4, and N7) and SANS blunted affect, avolition and anhedonia domain scores. Given the limited effects of PANSS positive scale and ESRS scores on the reduction of the negative scale scores in PREG-treated patients, it is possible to hypothesize that adjunctive PREG might reduce primary negative symptoms.
Second, adjunctive PREG reduced the severity of PANSS negative symptoms in weeks 6 and 8 of therapy, especially among patients who were not concomitantly treated with mood stabilizers. While somewhat speculative, it may be suggested that PREG augmentation has an interaction with mood stabilizer agents that are administered in both SZ, and SA disorder. This assumption seems to be supported by preclinical findings.[28, 29] Furthermore, neurosteroids and antiepileptic agents may exert an effect via GABA and glutamate. For instance, PREG modulates inhibitory synaptic transmission by enhancing GABAA receptor desensitization. Much more research is needed to test these assumptions.
Third, antipsychotic agents, DSM-IV diagnosis, side-effects, and sex did not associate significantly with effect of PREG augmentation. General functioning and extrapyramidal side-effects were not affected by adjunctive PREG in our sample. The observed differences in the findings between our previous 8-week trial with PREG (30 mg/day) and the present sample, particularly with regard to negative symptoms, may be explained by significant differences in background characteristics (age, predominance of male subjects, and illness duration: 15.1 vs 2.5 years), sample sizes (14 vs 25), and severity of clinical condition (at baseline, PANSS subscale scores were substantially lower in the present sample compared to our previous trial). There is clear evidence of age-related changes in circulating neurosteroids, such as DHEA, and DHEAS, PREG, and PREGS.[31, 32] The present study suggests that PREG did not induce amelioration of extrapyramidal side-effects, measured with ESRS, among recent-onset SZ/SA disorder patients contrary to findings from a study of chronic SZ/SA. This discrepancy may be explained, at least in part, by differences in the populations studied.
Fourth, although one new extrapyramidal adverse effect was observed, PREG treatment was generally well tolerated, confirming previous trials with PREG.[11, 12]
Although it remains poorly understood at this stage, the modulatory effect of PREG and its sulfate on GABAA, NMDA, sigma-1, cholinergic, and dopamine systems[1-4] may account for PREG's influence on clinical improvement. Another possibility is that PREG regulates the growth of neurons and cerebral brain-derived neurotrophic factor (BDNF) levels, enhances the myelination and synaptogenesis in the CNS, and demonstrates neuroprotective properties.[33, 34] The potential effect of adjunctive PREG on negative symptoms may be of considerable clinical interest, and may also expand our knowledge of the mechanisms involved in the development of negative symptoms. Further testing of this hypothesis is warranted.
The present findings should be accepted cautiously. The relatively modest sample size of this trial should be carefully examined before generalizing the findings to other groups. Limitations of this study also include the relatively short duration of the study. Long-term, large-scale studies are required to obtain greater statistical significance and more confident clinical generalization. In addition, it would be important in larger sample sizes to investigate whether any interaction exists between PREG and any specific medication and to compare responses to PREG in those receiving typical and atypical antipsychotics within the context of a standardized medication regimen.
On the basis of these results, we conclude that adjunctive pregnenolone significantly reduces PANSS negative scale and SANS domain scores in comparison to placebo among patients with recent-onset SZ and SA disorders. As we have some concerns about clinical versus statistical significance, larger studies should be conducted to establish the potential utility of the treatment.