Management of Treatment-Refractory Schizophrenia

September 30, 2014

Because cognitive and negative symptoms have the greatest impact on overall recovery, interdisciplinary strategies that target these symptoms are necessary. This article offers details.

Decades after the introduction of antipsychotic medication, schizophrenia continues to be among the most severe psychiatric illnesses-and a challenge for clinicians and patients to overcome. The core pathological domains of schizophrenia include positive symptoms (delusions, hallucinations), negative symptoms (avolition, anhedonia, asociality), and cognitive symptoms (verbal learning, working memory). Treatment can be further complicated by medical and psychiatric comorbidities, which influence treatment options.

Schizophrenia can be refractory to treatment despite the use of well- intentioned and thoughtful therapies. While estimates vary, up to 70% of patients are reported to have suboptimal outcomes.1,2 Treatment resistance is typically characterized by the failure of symptoms to remit after more than 2 antipsychotic trials of adequate duration (at least 6 weeks), although it has been suggested that the definition include the continuation of symptoms after one medication fails to achieve satisfactory remission.1

Whether due to the limitations of current medication options or the difficulty in engaging patients in participating adequately in their care, the deck is often stacked against patients in their battle for illness recovery. As psychiatrists, we work to enhance the odds for patients but often are held back by numerous factors, including systemic and technological barriers.

Because schizophrenia is diagnosed after the onset of psychotic symptoms, it can be difficult to improve the multifaceted deficits that are present in addition to the pathognomonic signs. Once psychosis has developed, brain changes have occurred that are difficult to fix. Moreover, multiple prognostic factors, such as duration of untreated psychosis, yield differential responses to treatment and likelihood of remission. In fact, there may be different types and trajectories of schizophrenia beyond our current characterizations and treatment algorithms.3 Despite these obstacles, there is much that can be done for patients, including those who have symptoms that persist despite multiple treatment efforts.

Typical goals of care focus on the amelioration of positive symptoms. Antipsychotic medications have demonstrated effectiveness on these domains, although positive symptoms are only one aspect of schizophrenia. Treatment algorithms have historically focused on these symptoms, but current guidelines highlight the need to think beyond these symptoms and pursue more comprehensive treatment. Because cognitive and negative symptoms have the greatest impact on overall recovery, interdisciplinary strategies that target these symptoms are necessary.

Refractory positive symptoms

Clozapine has long been the mainstay of treatment for patients with refractory schizophrenia.4 Considered to be the most effective antipsychotic in this subset of patients, its use is limited primarily by significant adverse effects. Nationally, 2.5% of antipsychotic prescriptions are for clozapine, and among patients who have treatment-resistant schizophrenia, 5.5% of antipsychotics prescribed are clozapine.5

Treatment algorithms suggest that clozapine be initiated after 2 antipsychotic medication trials fail after 6 weeks of treatment.6 Despite the guidelines, clozapine is often started later than the recommendation, if at all. Findings indicate that clozapine is more effective in refractory patients. Clozapine is also associated with a decreased risk of suicide.7 Fewer patients receive clozapine than should; thus, those who do not receive it more likely continue to experience suboptimal outcomes.5

Clozapine should be started slowly and the dose increased gradually to minimize the risk for agranulocytosis. Initially, patients must have a complete blood cell count weekly to monitor for any clinically significant changes in white blood cell counts, and all patients must be entered in a clozapine registry. In addition, clinicians should monitor closely for constipation and make sure to prescribe an aggressive bowel regimen because the anticholinergic effects can lead to colon perforation in patients who are severely affected. Myocarditis should also be considered in patients who complain of chest pain or tachycardia, particularly in the first month of treatment.8 There are limited options for treatment of clozapine-induced sialorrhea, for which glycopyrrolate may be used.9

The adverse effects most likely to complicate clozapine treatment, however, are metabolic. Clozapine is associated with significant weight gain, insulin resistance, and dyslipidemia. These symptoms must be monitored closely, often in partnership with the primary care physician, and may limit long-term viability of clozapine treatment.10

Despite the increased risk of metabolic effects with clozapine and olanzapine, all antipsychotics have been associated with weight gain, dyslipidemia, and insulin resistance. When these symptoms limit antipsychotic treatment, there are few evidence-based options, since behavioral methods have been shown to be of limited effectiveness out-side of the hospital.11 Metformin has been shown to benefit weight and lipid levels when used in conjunction with olanzapine, and it may be modestly effective when used as an adjunct to clozapine or other agents.12

Because clozapine is a “treatment of last resort,” a common concern is what to do when clozapine is not an option. Patients who experience considerable adverse effects may be able to try a rechallenge with clozapine in circumstances in which changes in adjunctive treatments may decrease the risk of reexperiencing the same effects. For example, in patients in whom agranulocytosis develops, a rechallenge of clozapine in conjunction with either lithium or granulocyte colony-stimulating factor augmentation (and with hematology consultation) can be attempted with very close follow-up; this may be successful in up to 70% of cases. There are also case reports of successful rechallenge after neuroleptic malignant syndrome and after episodes of myocarditis.13

Of greater clinical concern, however, is what to do when clozapine is ineffective. For this situation, there are limited data to guide treatment. A primary factor is what the effect of adherence is to the overall success of the intended medication. Estimates vary, but it has been shown that close to 40% of medications prescribed are not taken by patients.14 A common and often effective strategy to target nonadherence is to use long-acting injectable medications. These medications require administration every 2 to 4 weeks and may decrease adverse effects while ensuring more even symptom control. The decision to start a long-acting injectable medication must be determined on an individual basis while weighing the risks and benefits.15

When a long-acting injectable is ineffective or not a viable option, other strategies can be considered. The most common techniques include combining medications (polypharmacy) or using higher doses of single medications. There is limited evidence to guide either of these decisions, thus it is necessary to work with patients and families to determine which techniques are more likely to be effective.

When considering higher than usual doses of medications, adverse effects become of great concern. Even medications that do not frequently cause extrapyramidal symptoms at lower doses, such as olanzapine, may cause them at higher doses.16 Similarly, issues of QT prolongation, hyperprolactinemia, sedation, and metabolic adverse effects require more vigilance at higher than typical doses.17

There are virtually unlimited possible combinations of medications available; thus, specific data for many of these combinations are not available. The use of polypharmacy is common, and in many situations it is effective. Current studies have generally been short, and thus the finding that polypharmacy is effective still needs to be better studied.18 The choice of agents is frequently guided by clinical intuition, and strategies often include combining 2 antipsychotic medications, or an antipsychotic plus an anxiolytic, mood stabilizer, or antidepressant medication.19

There is some evidence for the benefits of combining antipsychotic medications, particularly as augmentation of clozapine. Small studies have shown positive results for augmenting clozapine with aripiprazole or risperidone, but those effects diminish in aggregated data (ie, meta-analysis).20 The initially promising results seen with the combination of clozapine with lamotrigine or topiramate have also not shown significant effects in meta-analysis. Small studies of citalopram and mirtazapine have shown promise for improvement of negative symptoms, but the results are too limited to generalize.20 Ultimately, the lack of evidence requires clinicians to consider options broadly and judiciously and to monitor the effects.21

Nonpharmacological techniques

Pharmacological interventions are generally limited to improvement of positive symptoms; however, treatment options must include interventions aimed at treating the other symptoms of schizophrenia. Promising psychotherapy techniques, particularly cognitive-behavioral therapy (CBT), have demonstrated benefits on multiple symptom domains, including both positive and negative symptoms.22 The effects of CBT persist over time, although the effects begin to wane once the treatment is withdrawn or terminated. A significant limitation of CBT outside of the research setting is that it is labor-intensive.23 Other modalities, including group treatments, also show promise.24 Ultimately, the use of adjunctive psychotherapy is likely to be beneficial, much in the same way as the treatment of complex mood disorders and other psychiatric conditions.

Neurostimulation techniques are also available for the treatment of refractory symptoms. Because these are generally reserved for refractory patients, the data sometimes appear less promising than might be if used on all patients. Electroconvulsive therapy (ECT) has been used to treat schizophrenia for decades. The benefits of ECT have been seen over a wide range of psychotic disorders, but ECT has been most effective in treating refractory schizophrenia when given in conjunction with clozapine or another antipsychotic.25

Newer techniques utilize the benefits of electrical or magnetic stimulation without inducing a seizure. Repetitive transcranial magnetic stimulation (rTMS) has shown the greatest effect on treating auditory hallucinations, and there is some evidence that supports its use in treating negative symptoms. With rTMS, one can specifically target the left temporoparietal cortex to focus on auditory hallucinations or the dorsolateral prefrontal cortex for negative symptoms. Duration of treatment was not seen to correlate with effect size in targeting positive symptoms, although in the treatment of negative symptoms, there was greater improvement when treatment lasted beyond 3 weeks.26

Transcranial direct current stimulation (tDCS) is similarly able to concentrate an electrical current to specific brain regions. Having shown promise in altering N-methyl-D-aspartate glutamatergic activity, tDCS is being investigated for cognitive enhancement. In addition, promising results were seen when positive symptoms were targeted. However, additional studies are needed to better determine its over-all effectiveness.27

Using multiple modalities is often the key to successful treatment of patients with refractory illness. Most patients cite goals beyond simply the amelioration of symptoms, and understanding their desires is critical to making treatment decisions.28 Combining treatments may include 2 or more modalities to achieve synergistic benefits. Typically, an antipsychotic would be combined with nonpharmacological treatments, including psychosocial interventions. These treatments should include interventions to help with smoking cessation or improving overall health, including weight management.29 This should also include interventions that target occupational, social, and cognitive functioning.

Assertive community treatment models are effective in bringing care to patients who may otherwise have difficulty in accessing care on their own.30 Achieving recovery from schizophrenia means something different for each patient, and focusing treatments to work toward specific goals should begin at the start of treatment.31


Despite our best efforts to treat schizophrenia to remission of symptoms, it remains difficult to achieve optimal recovery in most patients. Antipsychotic medications are most effective at treating positive symptoms, but they do not generally improve other core symptoms. Multimodal treatments (eg, psychosocial interventions) are important to consider to achieve the best outcomes. Working together with patients and other stakeholders is critical to understanding the individual needs and goals of patients to best focus limited resources most efficiently.


Dr Ballon is Clinical Assistant Professor and Director of a new clinical program in psychosis in the department of psychiatry and behavioral science at the Stanford University School of Medicine, Stanford, Calif. He reports that he has received investigator-initiated research support from Novartis. Dr Hu is Clinical Associate Professor in the department of psychiatry and behavioral science at the Stanford University School of Medicine. He has received investigator-initiated research support from Novartis.


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