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Treatment Resistance in Schizophrenia: The Role of Alternative Therapies

Treatment Resistance in Schizophrenia: The Role of Alternative Therapies

In 1931, Gananath Sen and Kartick Chandra Bose1 reported on the use of an alkaloid extract from the Rauwolfia serpentina plant in the treatment of hypertension and "insanity with violent maniacal symptoms." They noted that dosages "of 20 to 30 grains of the powder twice daily produce not only a hypnotic effect but also a reduction of blood pressure and violent symptoms . . . within a week usually the patient's senses are restored, though he may show some mental aberrations."1

Outside of India, however, Sen and Bose's observations on the use of rauwolfia for psychotic disorders were generally ignored. It was not until 1954, when Nathan Kline2 reported that both whole root rauwolfia extract and reserpine—a purer preparation—seemed to be somewhat more effective than placebo in more than 400 inpatients with neuropsychiatric conditions, that clinicians in the West took notice. Although it soon became apparent that phenothiazines were generally more tolerable than reserpine, and even after our enthusiastic embrace of clozapine, a respected 1991 review3 still listed reserpine as 1 of 8 reasonable, evidence-based treatment options for persons affected with the refractory symptoms of schizophrenia.

Was Sen and Bose's root extract treatment "alternative"? Alternative is a fuzzy term; this article will include information on vitamins, dietary supplements, herbal treatments, and—quite broadly—"other." Virtually all of these approaches are meant to be adjunctive and can be considered as additions to traditional antipsychotic therapy, rather than replacing it.

A variety of treatments, some of them quite novel at the time, have been used for schizophrenia over the years. The Figure provides a brief timeline for the introduction of a number of such therapies.

Orthomolecular psychiatry

In the 1960s, the idea of treating patients with mental illnesses with high doses of vitamins became popular. Within the realm of what Linus Pauling christened "orthomolecular psychiatry," Hoffer and Osmond4 championed the use of a high dose of vitamin B3 (niacin) and suggested that there was some connection between schizophrenia and the vitamin-deficiency disorder pellagra, which can present with a variety of psychiatric symptoms. However, conceptual problems with this hypothesis and negative findings in controlled studies diminished the fervor for this vitamin intervention.5,6 A 1991 review of 53 trials that tested niacin or vitamin B6 in a variety of psychiatric disorders found serious methodologic deficiencies in virtually all of the studies.7

Mainstream approaches to treatment resistance

A page was turned when Kane and associates8 published results from a landmark study of clozapine that demonstrated real hope for persons with treatment-resistant symptoms associated with schizophrenia. The researchers used a demanding operationalized definition of treatment resistance for the study that included significant psychotic pathology in the face of at least 3 unsuccessful trials of different neuroleptics at high doses for a minimum of 6 weeks in the previous 5 years. The study findings showed that clozapine was superior to chlorpromazine not only in treating the positive symptoms of treatment-resistant schizophrenia but also in treating the recalcitrant negative symptoms. Previously, clinicians may have been satisfied to treat a person who had an acute exacerbation of schizophrenia to the point where delusions and hallucinations were minimized and he or she was stable and dischargeable. This study raised the bar for treatment goals.

More recently, cognitive symptoms were being appreciated as not only critical core symptoms of schizophrenia, but, along with negative symptoms, a principal cause of the functional disability associated with this disorder.9-12 It is a major clinical advance that atypical antipsychotics, such as clozapine, olanzapine, and risperidone, have been found to ameliorate positive, negative, and cognitive symptoms, and symptoms of excitement/agitation and depression/anxiety in schizophrenia.13

The realization that other symptom domains are treatable has expanded what we expect of ourselves as psychiatrists in treating schizophrenia, and this is reinforced by the growth of the recovery model for treatment. This more appropriate biopsychosocial perspective casts a wider net for how we view treatment-resistant symptoms. Early successes still left patients with much that needed to be addressed regarding symptoms and functionality. It is now accepted that residual symptoms should be viewed as treatment resistant and worthy of appropriate attention.

The current mainstream allopathic-somatic approach focuses on treating patients who have schizophrenia with an atypical antipsychotic; if several of these fail, a trial of clozapine should be considered because it may be specifically more effective in reducing symptoms of aggression14 and suicidality.15,16

Adjunctive electroconvulsant therapy is an approach that is clearly beneficial for treating positive symptoms or agitation, although not always practical.17 Low-frequency transcranial magnetic stimulation is sometimes effective for intractable hallucinations18 and cognitive-behavioral therapy (now a standard of care in the United Kingdom19) and cognitive remediation20 address particular refractory areas of psychopathology. Nonetheless, these strategies often leave significant residual symptoms because of lack of response, adverse effects, or patients' rejection of particular treatments.

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