Integrative Management of Schizophrenia

May 13, 2014

Select natural products have been evaluated as adjunctive agents that may be combined with conventional antipsychotics, with promising preliminary findings. Music therapy, meditation, and mindfulness training may improve quality of life for individuals with schizophrenia. Details here.

Available antipsychotics are probably moderately more effective than placebos and are associated with serious adverse effects, which result in poor adherence. While there is limited evidence for nonpharmacological therapies as monotherapies in the treatment of schizophrenia, select natural products have been evaluated as adjunctive agents that may be combined with conventional antipsychotics, with promising preliminary findings. Moreover, music therapy, meditation, and mindfulness training may improve the quality of life in individuals with schizophrenia.

Limitations of conventional pharmacological treatments

Currently available antipsychotics antagonize dopamine D2 receptors that result in CNS changes believed to mediate anti-hallucinatory and anti-delusional effects. The D2-blocking property of typical antipsychotics is associated with increased serum prolactin levels and serious neurological adverse effects, including extrapyramidal syndrome, parkinsonism, akathisia, and tardive dyskinesia (TD). Newer atypical antipsychotics, such as clozapine and risperidone, antagonize both D2 and serotonin 2A receptors.

Meta-analyses on the use of oral antipsychotics for treatment of schizophrenia confirm that antipsychotics are moderately more effective than placebo, but their adverse effects are largely responsible for medication discontinuation.1-3 It is estimated that medication adherence is poor in as many as 75% of patients.4 Although clozapine, olanzapine, and risperidone may be more effective than other oral antipsychotics, clozapine and olanzapine are associated with the greatest incidence of adverse metabolic effects and weight gain. The limitations and safety issues associated with available antipsychotics invite consideration of promising nonpharmacological therapies.

Antioxidants and ω-3 fatty acids

Omega-3 fatty acids, especially 2 to 4 g of eicosapentaenoic acid (EPA) daily, alone or in combination with antipsychotics, may improve auditory hallucinations, paranoia, and confused thinking that often occur in patients with schizophrenia while they mitigate antipsychotic adverse neurological effects. Antipsychotics such as haloperidol increase oxidative stress, resulting in widespread neuronal injury in the brain and interference with the beneficial effects of conventional drug treatments of schizophrenia. Dietary supplementation including antioxidants and ω-3 fatty acids may improve symptoms of psychosis.

In a 4-month open-label study, 17 patients with schizophrenia were treated with vitamin C (1000 mg/d), vitamin E (400 IU bid), and ω-3 fatty acids (1000 mg/d) while they continued to take oral haloperidol.5 Superoxide dismutase levels were significantly lower at the end of the study, reflecting an overall reduction in oxidative stress. Patients also reported significant reductions in akithisia.

EPA augmentation may be an effective preventive strategy in persons at high risk for schizophrenia or in the early phase of psychotic illness but not as a treatment for patients with established schizophrenia or other psychotic disorders. Once there is disease progression, supplementation with EPA does not cor-rect widespread neuropathological changes in the brain.

In a small placebo-controlled trial, EPA had significant antipsychotic efficacy when used as a monotherapy for a first psychotic episode.6 EPA used as an adjunct to an antipsychotic resulted in fewer positive symptoms compared with placebo; however, response to adjunctive therapy was not significantly greater than response to placebo in first-episode schizophrenia.

Patients who received EPA required lower antipsychotic doses for adequate symptom control and reported fewer sexual and neurological adverse effects compared with placebo augmentation of an antipsychotic.7 These findings suggest that EPA augmentation may be a reasonable option for improving the tolerability of conventional antipsychotics, especially when treating first episodes.

Use of ω-3 fatty acids in patients with established schizophrenia is less promising. A meta-analysis of placebo-controlled studies of EPA augmentation in patients with chronic schizophrenia or other psychotic disorders found no evidence of greater benefit with EPA augmentation compared with antipsychotic medications alone.8

Possible explanations of negative findings include small study size, absence of clinical efficacy of EPA supplementation in chronic schizophrenia, and a “ceiling effect” associated with concurrent treatment with antipsychotics. Also, combinations of different fatty acids may be more effective than EPA alone, dietary differences or other sociodemographic factors may have confounded outcomes, and ω-3 fatty acid augmentation may be effective only as a preventive agent or following a first psychotic episode.

In a 12-week placebo-controlled study, individuals considered to be at extremely high risk for schizophrenia were randomized to ω-3 fatty acids (1.2 g/d) or placebo.9 At study end, 11 participants (27.5%) in the placebo group had transitioned to a psychotic disorder compared with 2 (5%) in the ω-3 group. Participants who received ω-3 fatty acids had significantly fewer positive and negative psychotic symptoms and improved global functioning compared with those in the placebo group.

The benefits of EPA supplementation may include accelerated treatment response and more effective antipsychotic doses with fewer adverse effects. Pending confirmation of preliminary findings by large, well-controlled trials and clarification of the optimal form and dosage of ω-3 fatty acids, it is reasonable to recommend ω-3 supplementation to individuals with schizophrenia.

Vitamin E and melatonin

Provisional evidence shows that vitamin E may slow the rate of deterioration of TD but not that vitamin E improves symptoms of antipsychotic-induced TD once it is established.10 Melatonin may indirectly enhance antipsychotic efficacy via anti-inflammatory and antioxidative effects. Research findings suggest that melatonin improves sleep disturbances commonly seen in patients with schizophrenia and lessens the severity of TD and metabolic syndrome associated with antipsychotics.11

Hormones

Differences in the incidence and course of schizophrenia in men and women suggest that estrogen may protect against the development of schizophrenia and other psychotic disorders in genetically predisposed individuals. Findings from placebo-controlled trials indicate that estrogen may be an effective adjuvant to antipsychotics in the treatment of schizophrenia. The mechanism of action may involve antagonism of the same neurotransmitter systems targeted by the atypical antipsychotics.

A Cochrane systematic review found inconclusive evidence for adjunctive estrogen in patients with schizophrenia12; however, more recent studies report significant clinical improvement using estradiol for both positive and negative symptoms.13,14 Lower therapeutic doses of antipsychotics with adjuvant estradiol resulted in fewer adverse effects and improved adherence.15

DHEA (dehydroepiandrosterone) is the most abundant hormone in the body and is required for the synthesis of several important hormones. DHEA affects several brain neurotransmitters, resulting in improvement in symptoms of schizophrenia and cognitive impairment that often accompanies the disorder. Combining DHEA with a conventional antipsychotic may be more effective than an antipsychotic alone.

Patients who received 200 mg/d of DHEA had greater improvement in cognitive functioning than did those who received placebo.16 DHEA may be especially beneficial for improving symptoms of apathy and social withdrawal that often accompany schizophrenia. There is evidence that DHEA may also be beneficial for depressed mood and anxiety that occur frequently in patients with schizophrenia.

DHEA can cause nervousness and agitation and is best taken in the morning to reduce the risk of insomnia. Men who have benign prostatic hyperplasia or prostate cancer should consult with their physician before taking DHEA. More studies are needed to confirm these preliminary findings and determine safe and effective hormonal treatment strategies.

American ginseng (Panax quinquefolius) and ginkgo (Ginkgo biloba)

Following drug treatment, persons with schizophrenia frequently experience severe deficits in working memory that interfere with functional improvement. In a randomized, 4-week, placebo-controlled trial, patients with schizophrenia who received a standardized extract of American ginseng showed significantly greater improvements in visual working memory than did patients who received placebo.17

Persons who were taking American ginseng reported significantly fewer neurological adverse effects after 4 weeks. Further studies are needed to confirm these findings and determine optimal dosing of American ginseng as an adjuvant to antipsychotics. Combining 360 mg of ginkgo with an antipsychotic may improve symptoms of schizophrenia more than taking an antipsychotic alone; however, more research is needed to confirm its possible beneficial effects and determine the most appropriate dose.18 The adjuvant use of ginkgo may also reduce the risk of movement disorders and other adverse neurological effects associated with antipsychotics.

Ginkgo increases the risk of bleeding and should not be taken before surgery or used by anyone who is taking blood-thinning medications.

Amino acids

Glycine is the smallest amino acid. High doses of glycine enhance global brain functioning in psychosis by helping to correct abnormal N-methyl-D-aspartate receptor functioning implicated in the pathogenesis of schizophrenia. Glycine may be especially effective against negative symptoms of schizophrenia, including apathy and social withdrawal.

Increased CNS glutamate levels are correlated with significant improvements in negative psychotic symptoms. Glycine at dosages of up to 60 g/d was shown to have beneficial effects on negative symptoms of schizophrenia.19 Patients who received up to 60 g/d of glycine in addition to a conventional antipsychotic experienced significant reductions in negative symptoms and improved global functioning.20

Glycine supplementation may also improve symptoms of depressed mood and impaired cognitive functioning, and this amino acid may lessen the adverse effects of antipsychotics. However, the therapeutic use of glycine requires large doses and there are safety concerns because there have been reports of acute psychosis with high doses of glycine.

The amino acid L-theanine reduces state anxiety by increasing alpha activity and stimulating synthesis of γ-aminobutyric acid. Noticeable anxiety reduction is generally achieved within 30 to 40 minutes, and effective dosages range from 200 to 800 mg/d. Preliminary findings suggest that L-theanine may be an effective adjuvant in the management of psychotic disorders. Patients with schizophrenia or schizoaffective disorder were randomized to receive L-theanine or placebo while continuing their antipsychotic medications.21 Patients who received L-theanine experienced moderate reductions in symptoms of psychosis and anxiety, and there were no differences in quality-of-life measures between the groups.

Large, placebo-controlled, randomized trials are needed to replicate these findings, address safety issues, and determine optimal dosing before glycine or L-theanine can be recommended for treatment of psychosis in acute mania or schizophrenia.

Mind-body approaches

A review of studies on mind-body approaches in schizophrenia and other psychotic disorders found substantial supportive evidence for music therapy, meditation, and mindfulness techniques as well as for multimodal therapies that combine different mind-body approaches.22 Findings for hypnosis, thermal or electromyographic biofeedback, dance therapy, drama therapy, and art therapy were inconclusive.

Most studies were limited by small size, absence of randomization, poor controls, and failure to use standardized outcomes measures. Because most studies involved group interventions, it was often challenging to isolate positive general effects of a support group from beneficial effects of a particular mind-body approach.

Although there is limited evidence for mind-body approaches in schizophrenia, these approaches may improve overall quality of life without associated risks and may be safely used in conjunction with antipsychotics. Therefore, it is reasonable to recommend mind-body approaches on a case-by-case basis depending on the patient’s level of functioning and motivation. As for the natural products reviewed above, large controlled studies are needed to confirm these preliminary findings before mind-body approaches can be generally recommended as mainstream treatments for persons with schizophrenia.

Disclosures:

Dr Lake is Former Chair of the International Network of Integrative Mental Health (www.INIMH.org) and practices integrative psychiatry on the California central coast. INIMH is a non-profit organization dedicated to advancing a global agenda for integrative mental health care through education, research, networking, and advocacy.

References:

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18. Zhang XY, Zhou DF, Zhang PY, et al. A double-blind, placebo-controlled trial of extract of Ginkgo biloba added to haloperidol in treatment-resistant patients with schizophrenia. J Clin Psychiatry. 2001; 62:878-883.

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21. Ritsner MS, Miodownik C, Ratner Y, et al. L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double-blind, placebo-controlled, 2-center study. J Clin Psychiatry. 2011;72:34-42.

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