Polypharmacy for Schizophrenia
Polypharmacy for Schizophrenia
The core positive and negative symptoms of schizophrenia are rarely the only targets for treatment. Mood, anxiety and obsessive-compulsive symptoms frequently require attention, but evidence for how best to approach these comorbidities is scant (see Table 1 ).
A parsimonious approach is to begin by optimizing antipsychotic monotherapy and psychosocial supports. An obvious but unproven approach is to treat these problems symptomatically by using treatments proven effective for mood and anxiety disorders. However, the need for internal validity when seeking regulatory approval for new medications leads to excluding people with comorbidities from clinical trials. For example, because people with schizophrenia are systematically excluded from trials of putative antidepressants and anxiolytics, the results of these trials only clearly apply to people without schizophrenia.
Whether the conventional treatments for common clinical symptoms such as depressed mood or anxiety are similarly effective for people with schizophrenia is not clear. Treating mood symptoms, for example, is particularly difficult in schizophrenia. Differentiating between negative symptoms and depression is clinically challenging, and, although there may be phenotypic overlaps, it is not known precisely what the pathophysiological differences are, and how those differences may affect the benefits of certain medications.
Although antipsychotic medications reduce ratings of negative symptoms, this benefit is thought primarily to result from improvement of secondary negative symptoms and a resulting decrease in social withdrawal. In the absence of proven treatments for primary negative symptoms, or those that do not improve with antipsychotic treatment alone, antidepressants are often considered for use. Evidence is varied on the effectiveness of antidepressants for negative symptoms. In a meta-analysis, a modest effect size of 0.48 was shown overall in favour of using antidepressants, though with the removal of three outlier results the effect size dropped to 0.33. Notably, in this meta-analysis, more studies showed inconclusive benefit than those that showed statistically significant benefits for antidepressants. Moreover, the only commonly used antidepressant to show a benefit was fluoxetine (trazodone and ritanserin were also statistically significant in one study each) and did so in only one of four reported trials. Other antidepressants failed to show a distinct and significant benefit when data were combined. A study of escitalopram conducted after the above systematic review also failed to demonstrate substantial benefits. A single small study using mirtazapine demonstrated small benefit for mirtazapine on negative symptoms, but individuals on mirtazapine gained 5 kg more than those on placebo.
Antidepressants may yield benefits beyond direct symptomatic improvements in people diagnosed with schizophrenia. A recent pharmacoepidemiology study from Finland found antidepressants to be associated with decreased mortality. The finding appears to extend beyond just decreased suicide rates. In the same study, benzodiazepines were associated with increased mortality, which was also not related to increased suicide rates. The findings of this observational study require replication and need to be understood in the context of possible confounds, but highlight the significant impact, positive and negative, that additional medications may have in addition to measurable symptom differences.
Benzodiazepines are frequently used to target symptoms, including anxiety and insomnia. Although rates of benzodiazepine augmentation likely vary around the world, a recent report from Taiwan indicated that nearly 80% of schizophrenia patients were receiving benzodiazepines over the course of 1 year. Large differences in rates of benzodiazepine use between close geographic areas have been described, though this small area variation remains to be fully described for people with schizophrenia. The significant variations in use highlight the lack of evidence-based recommendations regarding benzodiazepines. The most recent systematic review data from the Cochrane group do not find evidence that benzodiazepines are useful beyond short-term sedation in schizophrenia. However, the lack of evidence in support of benzodiazepines does not rule out their use, as there are circumstances in which they can be helpful. The recent adverse mortality data, however, should be considered when using benzodiazepines, particularly if for more than short-term treatment.
The use of anticonvulsants, either to potentiate the effect of antipsychotic medications or to help prevent mania, has a long and complicated history. Valproic acid is sometimes used to accelerate the response to antipsychotics. Although helpful in the acute situation, there is no demonstrated benefit to this strategy after 6 months. This leads to the common polypharmacy scenario in which the regimen is no longer supported by research evidence, but, unless the patient is demonstrating side effects or other reasons to discontinue the treatment, a regimen that was apparently beneficial acutely is continued indefinitely. Although this seems innocuous, maintaining unnecessary medications exposes the patients to the potential for side effects on a treatment regimen with unclear benefit.
Lamotrigine is seen as an adjunctive medication for schizophrenia due to its mood-elevating properties. There have been few controlled studies of lamotrigine in schizophrenia other than for patients who did not respond fully to clozapine. In a recent meta-analysis, it was concluded that lamotrigine did not do better than placebo as a clozapine-augmentation strategy. Smaller studies have focused on topiramate. Initial reports show little benefit on topiramate on positive or negative symptoms. Cognitive side effects are common with topiramate and thus further limit its clinical utility.
Targeting Nonpsychotic Symptoms
The core positive and negative symptoms of schizophrenia are rarely the only targets for treatment. Mood, anxiety and obsessive-compulsive symptoms frequently require attention, but evidence for how best to approach these comorbidities is scant (see Table 1 ).
A parsimonious approach is to begin by optimizing antipsychotic monotherapy and psychosocial supports. An obvious but unproven approach is to treat these problems symptomatically by using treatments proven effective for mood and anxiety disorders. However, the need for internal validity when seeking regulatory approval for new medications leads to excluding people with comorbidities from clinical trials. For example, because people with schizophrenia are systematically excluded from trials of putative antidepressants and anxiolytics, the results of these trials only clearly apply to people without schizophrenia.
Whether the conventional treatments for common clinical symptoms such as depressed mood or anxiety are similarly effective for people with schizophrenia is not clear. Treating mood symptoms, for example, is particularly difficult in schizophrenia. Differentiating between negative symptoms and depression is clinically challenging, and, although there may be phenotypic overlaps, it is not known precisely what the pathophysiological differences are, and how those differences may affect the benefits of certain medications.
Although antipsychotic medications reduce ratings of negative symptoms, this benefit is thought primarily to result from improvement of secondary negative symptoms and a resulting decrease in social withdrawal. In the absence of proven treatments for primary negative symptoms, or those that do not improve with antipsychotic treatment alone, antidepressants are often considered for use. Evidence is varied on the effectiveness of antidepressants for negative symptoms. In a meta-analysis, a modest effect size of 0.48 was shown overall in favour of using antidepressants, though with the removal of three outlier results the effect size dropped to 0.33. Notably, in this meta-analysis, more studies showed inconclusive benefit than those that showed statistically significant benefits for antidepressants. Moreover, the only commonly used antidepressant to show a benefit was fluoxetine (trazodone and ritanserin were also statistically significant in one study each) and did so in only one of four reported trials. Other antidepressants failed to show a distinct and significant benefit when data were combined. A study of escitalopram conducted after the above systematic review also failed to demonstrate substantial benefits. A single small study using mirtazapine demonstrated small benefit for mirtazapine on negative symptoms, but individuals on mirtazapine gained 5 kg more than those on placebo.
Antidepressants may yield benefits beyond direct symptomatic improvements in people diagnosed with schizophrenia. A recent pharmacoepidemiology study from Finland found antidepressants to be associated with decreased mortality. The finding appears to extend beyond just decreased suicide rates. In the same study, benzodiazepines were associated with increased mortality, which was also not related to increased suicide rates. The findings of this observational study require replication and need to be understood in the context of possible confounds, but highlight the significant impact, positive and negative, that additional medications may have in addition to measurable symptom differences.
Benzodiazepines are frequently used to target symptoms, including anxiety and insomnia. Although rates of benzodiazepine augmentation likely vary around the world, a recent report from Taiwan indicated that nearly 80% of schizophrenia patients were receiving benzodiazepines over the course of 1 year. Large differences in rates of benzodiazepine use between close geographic areas have been described, though this small area variation remains to be fully described for people with schizophrenia. The significant variations in use highlight the lack of evidence-based recommendations regarding benzodiazepines. The most recent systematic review data from the Cochrane group do not find evidence that benzodiazepines are useful beyond short-term sedation in schizophrenia. However, the lack of evidence in support of benzodiazepines does not rule out their use, as there are circumstances in which they can be helpful. The recent adverse mortality data, however, should be considered when using benzodiazepines, particularly if for more than short-term treatment.
The use of anticonvulsants, either to potentiate the effect of antipsychotic medications or to help prevent mania, has a long and complicated history. Valproic acid is sometimes used to accelerate the response to antipsychotics. Although helpful in the acute situation, there is no demonstrated benefit to this strategy after 6 months. This leads to the common polypharmacy scenario in which the regimen is no longer supported by research evidence, but, unless the patient is demonstrating side effects or other reasons to discontinue the treatment, a regimen that was apparently beneficial acutely is continued indefinitely. Although this seems innocuous, maintaining unnecessary medications exposes the patients to the potential for side effects on a treatment regimen with unclear benefit.
Lamotrigine is seen as an adjunctive medication for schizophrenia due to its mood-elevating properties. There have been few controlled studies of lamotrigine in schizophrenia other than for patients who did not respond fully to clozapine. In a recent meta-analysis, it was concluded that lamotrigine did not do better than placebo as a clozapine-augmentation strategy. Smaller studies have focused on topiramate. Initial reports show little benefit on topiramate on positive or negative symptoms. Cognitive side effects are common with topiramate and thus further limit its clinical utility.
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