In the Journals

Analysis shows lacking evidence behind combination schizophrenia treatment

Some antipsychotic and psychotropic drug combinations were effective for schizophrenia in adults, according to meta-analyses; however, there was high risk for bias in study content.

“Although antipsychotic drugs are the cornerstone of treatment for schizophrenia, their effectiveness is limited, leaving many patients symptomatic despite ongoing antipsychotic therapy. As a result, alternative strategies, including switching antipsychotic drug treatments, dosage increases and combination treatments, are often used in schizophrenia,” Christoph U. Correll, MD, of Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, and colleagues wrote. “While adding medications to antipsychotic drug treatments is common when managing partial responses or treatment resistance in schizophrenia, no pharmacologic combination has been approved for this indication.”

Christoph U. Correll, MD
Christoph U. Correll

To assess efficacy of pharmacologic combination strategies of antipsychotic drugs for schizophrenia in adults, researchers assessed meta-analyses of randomized clinical trials comparing efficacy of antipsychotics combined with other antipsychotic and nonantipsychotic medications vs. placebo or antipsychotic monotherapy among adults with schizophrenia. Analysis included 29 meta-analyses of 42 combination strategies in 391 trials among 19,833 participants.

For total psychopathology, 14 of 32 agents combined with antipsychotics were significantly superior to controls. Standardized mean differences (SMD) ranged from –1.27 (95% CI, –2.35 to –0.19) for serotonin-noradrenaline reuptake inhibitors to –0.23 (95% CI, –0.44 to –0.02) for modafinil/armodafinil.

No pharmacological combinations with clozapine were superior to controls.

Regarding positive symptoms, six of 25 strategies were significantly more effective than controls, with SMDs ranging from –0.69 (95% CI, –1.2 to –0.18) for lamotrigine to –0.19 (95% CI, –0.37 to –0.01) for nonsteroidal anti-inflammatory drugs.

Only clozapine combinations containing glycine significantly outperformed controls for positive symptoms (SMD = –0.64; 95% CI, –1.11 to –0.17).

For negative symptoms, 12 of 26 strategies were superior to controls, with SMDs ranging from –1.4 (95% CI, –2.44 to –0.36) for serotonin-noradrenaline reuptake inhibitors to –0.26 (95% CI, –0.5 to – 0.02) for selective serotonin reuptake inhibitors.

None of the five combination strategies with clozapine outperformed placebo for negative symptoms.

Quality of methods was generally high, but quality of meta-analyzed studies was low, according to researchers.

Treatment recommendations correlated with effect size, but effect sizes were inversely associated with study quality.

“Meta-analyses of some combinations of an antipsychotic drug with a second psychotropic agent resulted in significant differences favoring their use over controls, but virtually all of the meta-analyzed study content revealed a high risk of bias,” the researchers wrote. “Therefore, none of the studied interventions had consistent empirical evidence for its use among an unselected population of patients with schizophrenia, yet future high-quality randomized clinical trials and patient-level meta-analyses could provide much needed clarity about moderators and mediators as well as patient subgroups that might benefit from specific pharmacologic combination strategies.” – by Amanda Oldt

Disclosure: Correll reports receiving consulting and advisorial fees and honoraria from Alkermes, Forum, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, Medavante, Medscape, Otsuka, Pfizer, ProPhase, Sunovion, Supernus, Takeda, and Teva; providing expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka; serving on a Data Safety Monitoring Board for Lundbeck and Pfizer; and receiving grant support from Takeda. Please see the study for a full list of relevant financial disclosures.

Some antipsychotic and psychotropic drug combinations were effective for schizophrenia in adults, according to meta-analyses; however, there was high risk for bias in study content.

“Although antipsychotic drugs are the cornerstone of treatment for schizophrenia, their effectiveness is limited, leaving many patients symptomatic despite ongoing antipsychotic therapy. As a result, alternative strategies, including switching antipsychotic drug treatments, dosage increases and combination treatments, are often used in schizophrenia,” Christoph U. Correll, MD, of Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, and colleagues wrote. “While adding medications to antipsychotic drug treatments is common when managing partial responses or treatment resistance in schizophrenia, no pharmacologic combination has been approved for this indication.”

Christoph U. Correll, MD
Christoph U. Correll

To assess efficacy of pharmacologic combination strategies of antipsychotic drugs for schizophrenia in adults, researchers assessed meta-analyses of randomized clinical trials comparing efficacy of antipsychotics combined with other antipsychotic and nonantipsychotic medications vs. placebo or antipsychotic monotherapy among adults with schizophrenia. Analysis included 29 meta-analyses of 42 combination strategies in 391 trials among 19,833 participants.

For total psychopathology, 14 of 32 agents combined with antipsychotics were significantly superior to controls. Standardized mean differences (SMD) ranged from –1.27 (95% CI, –2.35 to –0.19) for serotonin-noradrenaline reuptake inhibitors to –0.23 (95% CI, –0.44 to –0.02) for modafinil/armodafinil.

No pharmacological combinations with clozapine were superior to controls.

Regarding positive symptoms, six of 25 strategies were significantly more effective than controls, with SMDs ranging from –0.69 (95% CI, –1.2 to –0.18) for lamotrigine to –0.19 (95% CI, –0.37 to –0.01) for nonsteroidal anti-inflammatory drugs.

Only clozapine combinations containing glycine significantly outperformed controls for positive symptoms (SMD = –0.64; 95% CI, –1.11 to –0.17).

For negative symptoms, 12 of 26 strategies were superior to controls, with SMDs ranging from –1.4 (95% CI, –2.44 to –0.36) for serotonin-noradrenaline reuptake inhibitors to –0.26 (95% CI, –0.5 to – 0.02) for selective serotonin reuptake inhibitors.

None of the five combination strategies with clozapine outperformed placebo for negative symptoms.

Quality of methods was generally high, but quality of meta-analyzed studies was low, according to researchers.

Treatment recommendations correlated with effect size, but effect sizes were inversely associated with study quality.

“Meta-analyses of some combinations of an antipsychotic drug with a second psychotropic agent resulted in significant differences favoring their use over controls, but virtually all of the meta-analyzed study content revealed a high risk of bias,” the researchers wrote. “Therefore, none of the studied interventions had consistent empirical evidence for its use among an unselected population of patients with schizophrenia, yet future high-quality randomized clinical trials and patient-level meta-analyses could provide much needed clarity about moderators and mediators as well as patient subgroups that might benefit from specific pharmacologic combination strategies.” – by Amanda Oldt

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Disclosure: Correll reports receiving consulting and advisorial fees and honoraria from Alkermes, Forum, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, Medavante, Medscape, Otsuka, Pfizer, ProPhase, Sunovion, Supernus, Takeda, and Teva; providing expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka; serving on a Data Safety Monitoring Board for Lundbeck and Pfizer; and receiving grant support from Takeda. Please see the study for a full list of relevant financial disclosures.