Depressive symptoms are common early in the course of schizophrenia and are associated with poor quality of life, relapse, and suicidality. As a result, selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed, but their efficacy in first episode patients has not been studied. In a naturalistic study, prodromal patients treated with antidepressants were significantly less likely to progress to schizophrenia. SSRIs release brain derived neurotrophic factor (BDNF) which protects neurons from stress and stimulates neurogenesis. In schizophrenia, BDNF is dysregulated and BDNF genotype has been shown to predict cortical grey matter loss in first episode patients. These findings suggest that SSRI administration might protect against depression, relapse, and disease progression during the early course of the illness. Methods: We propose, in 100 first episode schizophrenia patients, a placebo-controlled, parallel-group, twelve month trial of citalopram added to risperidone treatment plus a psychoeducation protocol designed to enhance compliance and retention. Patients with significant depression or currently treated with an SSRI will be excluded from study and a CBT module targeting depression will be provided if depressive symptoms emerge during the trial. The primary outcome is depressive symptoms analyzed as the area under the curve per unit time. In addition, we will examine suicidality, negative symptoms, cognition, and relapse rates. Biomarkers will include BDNF Val66Met genotype, plasma BDNF concentrations, and gray matter volume to assess a possible relationship between SSRI treatment, enhanced BDNF activity, preservation of cortical gray matter, and improved clinical course. Significance: The evaluation of SSRI treatment for depressive symptoms, suicidal ideation and relapse in first episode patients is of considerable clinical importance. In addition, the potential role of SSRI-induced BDNF release in promoting neurogenesis and improving the course of the illness offers an exciting new direction for the pharmacology of schizophrenia.

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Depression is common in first episode schizophrenia and is associated with poor quality of life, suicidality and relapse. In a twelve month placebo controlled trial we will study the impact of citalopram in combination with risperidone and psychoeducation on the course of illness and will include as biomarkers, citalopram-induced elevation of plasma BDNF, BDNF genotype, and longitudinal measurement of gray matter volume.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1-ERB-F (02))
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Hillefors, MI
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Massachusetts General Hospital
United States
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Zeng, Botao; Ardekani, Babak A; Tang, Yingying et al. (2016) Abnormal white matter microstructure in drug-naive first episode schizophrenia patients before and after eight weeks of antipsychotic treatment. Schizophr Res 172:1-8
Cohen, Samuel M; Tsien, Richard W; Goff, Donald C et al. (2015) The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia. Schizophr Res 167:98-107