Long-term antidepressant treatment for negative symptoms in schizophrenia: The actions study
Background: The negative symptoms of schizophrenia represent defcien-cies in emotional responsiveness, motivation and socialization that tend to be persistent despite standard antipsychotic treatment. Two sub-domains of expressive defcits (affective fattening and poverty of speech) and avo-lition-amotivation for daily-life and social activities (apathy, amotivation and asociality) are recognized. Reviews of randomized controlled trials of adjunctive antidepressant treatment have concluded that the combination of antipsychotics and antidepressants may be effective in treating the negative symptoms of schizophrenia, but the amount and quality of the evidence available do not allow for any robust conclusion about the potential risks and benefts of such a strategy. Methods: ACTIONS was a multi-centre, double-blind, placebo-controlled, RCT with a 12-month follow-up, funded by the National Institute for Health Research, designed to test the clinical value and side effects of the SSRI antidepressant, citalopram, as an adjunct to continuing antipsychotic medication, in the management of persistent negative symptoms. Sixty-two eligible participants with an established diagnosis of schizophrenia who were maintained on a stable regimen of antipsychotic medication and who had persistent negative symptoms at a criterion level of severity were ran-domized to treatment with either placebo or citalopram at 20 mg a day for 48 weeks (with the clinical option at 4 weeks to increase the daily dose to citalopram 40 mg per day). Results: The trial under-recruited, partly because of concerns about cita-lopram cardiotoxicity raised by the Medicines & Healthcare products Regulatory Agency in 2011. The sample size achieved fell well short of the target recruitment of 358 participants, so the power of any statistical analysis to detect clinical or statistical meaningful signifcant differences between the treatment groups was limited. No therapeutic advantage was detected for adjunctive citalopram over 12 weeks or at 48 weeks in terms of improvement in quality of life or negative symptoms, except for modest improvement in the avolition-amotivation negative symptom domain at 12 weeks. There was no difference between the 2 treat-ment groups in the frequency or severity of adverse effects over the follow-up period and specifcally no difference in the duration of the QTc interval. Conclusion: The study fndings suggest that citalopram can have a positive effect, at least in the short-term, on the avolition-amotivation negative symptom domain, which is recognized as a critical barrier to psychoso-cial rehabilitation and better social and community functional outcomes. Comprehensive assessment of side-effect burden did not identify any serious safety or tolerability issues for citalopram. Further investigation of the viability and risk-beneft of long-term, adjunctive antidepressant treatment for the treatment of negative symptoms in schizophrenia may be warranted.