Letters COMMENT & RESPONSE
Conflict of Interest Disclosures: None reported.
Dose Reduction/Discontinuation for First-Episode Psychosis
1. Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry. 2013;70(9):913-920.
To the Editor We congratulate Wunderink et al1 for their longterm follow up of 7 years of patients with remitted firstepisode psychosis. Their results suggest superior rates of social functioning for patients who receive dose reduction/ discontinuation compared with maintenance treatment, despite a higher relapse rate during the first 3 years of treatment in the dose reduction/discontinuation group. We consider 2 possible explanations. One possibility may be that an attempt to stop medication gives such a boost to the confidence of patients (eg, less stigma) that this results in an improvement in social functioning. Another explanation could be a neurotoxic effect of antipsychotics. Some studies show results supporting this point. Harrow and Jobe2 took a critical stance with regard to long-term antipsychotic treatment based on 3 longitudinal studies of patients with schizophrenia unmedicated for years and showing better outcomes than comparator groups taking antipsychotics. Gleeson et al3 described an unexpected finding in a randomized clinical trial with a 30-month follow up of patients with first-episode psychosis. Patients in their specialist firstepisode psychosis program had superior medication adherence; however, psychosocial functioning deteriorated over time in the specialist program but not in the control group. In addition, there was an increase in negative symptoms compared with the control group. On the other hand, a meta-analysis published by Sampson et al4 advocated antipsychotic treatment. They found that antipsychotics, preferably as continuous treatment, are effective for relapse prevention without an apparent negative impact on social functioning. We conclude that the answer to the question of a potential negative impact on social functioning with prolonged use of antipsychotics is not clear despite great clinical relevance. The neurotoxicity hypothesis would be supported in case of a dose-response relationship. We would like to ask Wunderink and his research group whether they find a negative correlation between cumulative antipsychotic dose and psychosocial functioning. Wieteke S. Elzinga, MSc Peter F. J. Schulte, MD, PhD Author Affiliations: Mental Health Services North–Holland North, the Netherlands (Elzinga, Schulte). Corresponding Author: Wieteke S. Elzinga, MSc, Mental Health Services North–Holland North, Oude Hoeverweg 10, Alkmaar, Noord Holland 1816 BT, the Netherlands ([email protected]).
2. Harrow M, Jobe TH. Does long-term treatment of schizophrenia with antipsychotic medications facilitate recovery? Schizophr Bull. 2013;39(5): 962-965. 3. Gleeson JFM, Cotton SM, Alvarez-Jimenez M, et al. A randomized controlled trial of relapse prevention therapy for first-episode psychosis patients: outcome at 30-month follow-up. Schizophr Bull. 2013;39(2):436-448. 4. Sampson S, Joshi K, Mansour M, Adams CE. Intermittent drug techniques for schizophrenia. Schizophr Bull. 2013;39(5):960-961.
Mortality Risk of Mirtazapine: Guilt by Association? To the Editor In their analysis of psychopharmacology clinical trials data, Khan et al1 found that exposure to heterocyclic antidepressants (imipramine, amitriptyline, maprotiline, and mirtazapine) was associated with an increased mortality risk compared with placebo and with other psychotropic drugs. Although Khan et al1 stated that this finding was seen previously by Cheeta et al,2 the particular study by Cheeta et al observed no deaths associated with mirtazapine or maprotiline. Potential causes of drug-associated mortality include cardiovascular effects and seizures. The wider literature does not support an impression that mirtazapine is associated with significant adverse cardiovascular effects, and mirtazapine is less likely to be associated with seizures compared with maprotiline, imipramine, and amitriptyline.3 Other data have not found that mirtazapine is associated with a risk for death, even following an overdose.4 According to 2011 data from the National Poison Data System in the United States, 2765 human drug exposures resulting in death were documented and 1995 of these fatalities were judged to be related to the drug(s) involved.5 In the National Poison Data System database, deaths were analyzed and sorted according to the substance most likely responsible for the death (referred to as cause rank). Mirtazapine was involved in 22 of the 1995 fatalities (1.1%). The 22 cases all involved multiple drugs. Mirtazapine was judged to have a cause rank of 1 (deemed most likely responsible for the death) in only 1 case (involving alcohol, diazepam, and mirtazapine), although the relative contribution to the fatality was judged to be “probably responsible” rather than “undoubtedly responsible.”5 By lumping mirtazapine together with 3 other pharmacologically dissimilar drugs, the data analysis by Khan et al1 provided a misleading image of the relative mortality risk of mirtazapine. Reporting the mortality risk of mirtazapine alone would be more appropriate. Robert H. Howland, MD
jamapsychiatry.com
JAMA Psychiatry May 2014 Volume 71, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Florida User on 10/09/2016
585
Conflict of Interest Disclosures: None reported.
Dose Reduction/Discontinuation for First-Episode Psychosis
1. Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry. 2013;70(9):913-920.
To the Editor We congratulate Wunderink et al1 for their longterm follow up of 7 years of patients with remitted firstepisode psychosis. Their results suggest superior rates of social functioning for patients who receive dose reduction/ discontinuation compared with maintenance treatment, despite a higher relapse rate during the first 3 years of treatment in the dose reduction/discontinuation group. We consider 2 possible explanations. One possibility may be that an attempt to stop medication gives such a boost to the confidence of patients (eg, less stigma) that this results in an improvement in social functioning. Another explanation could be a neurotoxic effect of antipsychotics. Some studies show results supporting this point. Harrow and Jobe2 took a critical stance with regard to long-term antipsychotic treatment based on 3 longitudinal studies of patients with schizophrenia unmedicated for years and showing better outcomes than comparator groups taking antipsychotics. Gleeson et al3 described an unexpected finding in a randomized clinical trial with a 30-month follow up of patients with first-episode psychosis. Patients in their specialist firstepisode psychosis program had superior medication adherence; however, psychosocial functioning deteriorated over time in the specialist program but not in the control group. In addition, there was an increase in negative symptoms compared with the control group. On the other hand, a meta-analysis published by Sampson et al4 advocated antipsychotic treatment. They found that antipsychotics, preferably as continuous treatment, are effective for relapse prevention without an apparent negative impact on social functioning. We conclude that the answer to the question of a potential negative impact on social functioning with prolonged use of antipsychotics is not clear despite great clinical relevance. The neurotoxicity hypothesis would be supported in case of a dose-response relationship. We would like to ask Wunderink and his research group whether they find a negative correlation between cumulative antipsychotic dose and psychosocial functioning. Wieteke S. Elzinga, MSc Peter F. J. Schulte, MD, PhD Author Affiliations: Mental Health Services North–Holland North, the Netherlands (Elzinga, Schulte). Corresponding Author: Wieteke S. Elzinga, MSc, Mental Health Services North–Holland North, Oude Hoeverweg 10, Alkmaar, Noord Holland 1816 BT, the Netherlands ([email protected]).
2. Harrow M, Jobe TH. Does long-term treatment of schizophrenia with antipsychotic medications facilitate recovery? Schizophr Bull. 2013;39(5): 962-965. 3. Gleeson JFM, Cotton SM, Alvarez-Jimenez M, et al. A randomized controlled trial of relapse prevention therapy for first-episode psychosis patients: outcome at 30-month follow-up. Schizophr Bull. 2013;39(2):436-448. 4. Sampson S, Joshi K, Mansour M, Adams CE. Intermittent drug techniques for schizophrenia. Schizophr Bull. 2013;39(5):960-961.
Mortality Risk of Mirtazapine: Guilt by Association? To the Editor In their analysis of psychopharmacology clinical trials data, Khan et al1 found that exposure to heterocyclic antidepressants (imipramine, amitriptyline, maprotiline, and mirtazapine) was associated with an increased mortality risk compared with placebo and with other psychotropic drugs. Although Khan et al1 stated that this finding was seen previously by Cheeta et al,2 the particular study by Cheeta et al observed no deaths associated with mirtazapine or maprotiline. Potential causes of drug-associated mortality include cardiovascular effects and seizures. The wider literature does not support an impression that mirtazapine is associated with significant adverse cardiovascular effects, and mirtazapine is less likely to be associated with seizures compared with maprotiline, imipramine, and amitriptyline.3 Other data have not found that mirtazapine is associated with a risk for death, even following an overdose.4 According to 2011 data from the National Poison Data System in the United States, 2765 human drug exposures resulting in death were documented and 1995 of these fatalities were judged to be related to the drug(s) involved.5 In the National Poison Data System database, deaths were analyzed and sorted according to the substance most likely responsible for the death (referred to as cause rank). Mirtazapine was involved in 22 of the 1995 fatalities (1.1%). The 22 cases all involved multiple drugs. Mirtazapine was judged to have a cause rank of 1 (deemed most likely responsible for the death) in only 1 case (involving alcohol, diazepam, and mirtazapine), although the relative contribution to the fatality was judged to be “probably responsible” rather than “undoubtedly responsible.”5 By lumping mirtazapine together with 3 other pharmacologically dissimilar drugs, the data analysis by Khan et al1 provided a misleading image of the relative mortality risk of mirtazapine. Reporting the mortality risk of mirtazapine alone would be more appropriate. Robert H. Howland, MD
jamapsychiatry.com
JAMA Psychiatry May 2014 Volume 71, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Florida User on 10/09/2016
585
