Antidepressants for the negative symptoms of schizophrenia

Rummel, Christine; Kissling, Werner; Leucht, Stefan

doi:10.1002/14651858.cd005581

Cited by 32 publications

(32 citation statements)

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“…Indeed, the fact that both clozapine, a serotonergic antagonist, and SSRI, a serotonin agonist, are effective is paradoxical, and although the pharmacological properties predict that combining clozapine with SSRI will lead to antagonism, clinical studies show that effectiveness may be improved. 9,37 To account for these characteristics, we hypothesized that chronic treatment with the SSRI-antipsychotic combination produces unique biochemical changes in the brain, different from those of the individual drugs, and that these mediate the enhanced clinical effectiveness. 37 We argued that molecular changes unique to the drug combination and different from the action of individual drugs encompass those changes that are relevant to clinical effectiveness of the combined treatment and to the psychopathology of negative symptoms.…”

Section: The Ssri-antipsychotic Combination As a Paradigm For Investimentioning

confidence: 99%

Multifunctional Pharmacotherapy: What Can We Learn from Study of Selective Serotonin Reuptake Inhibitor Augmentation of Antipsychotics in Negative-Symptom Schizophrenia?

et al. 2009

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Summary: Many patients suffering from major psychiatric disorders do not respond adequately to monotherapy and require additional drugs. To date, there are no objective guidelines for deciding which combination may be effective, and the choice is based on previous clinical experience and on trial and error. Even when combination drugs are effective, the biochemical mechanisms responsible for the value-added effect are unknown. Understanding the mechanism of such synergism may provide a rational basis for choosing drug combinations and for developing more effective drugs. In schizophrenia, negative symptoms respond poorly to antipsychotics, but may improve when these are augmented with selective serotonin reuptake inhibitors (SSRI). This augmenting effect cannot be explained by summating the pharmacological effects of the individual drugs. We proposed that the study of SSRI augmentation can serve as a window to understanding the biochemical mechanisms of clinically effective drug synergism. In a series of studies we identified unique biochemical effects of the combination, different from each individual drug, and proposed that some of these are involved in mediating the clinical effect. Here we review some of the findings and propose that the mechanism of action involves regionally selective modulation of the GABA system. The evidence indicates that the SSRI antidepressant-antipsychotic combination may be a useful paradigm for studying therapeutically effective synergistic drug interactions in schizophrenia. Although as yet limited in scope, the findings of definable molecular targets for synergistic SSRIantipsychotic interaction provide new directions to inform future research and provide novel bio-molecular targets for drug development.

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Section: The Ssri-antipsychotic Combination As a Paradigm For Investimentioning

confidence: 99%

Multifunctional Pharmacotherapy: What Can We Learn from Study of Selective Serotonin Reuptake Inhibitor Augmentation of Antipsychotics in Negative-Symptom Schizophrenia?

et al. 2009

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“…One of the approaches to improve response of negative symptoms is augmentation of antipsychotic treatment with a selective serotonin reuptake inhibitor (SSRI) antidepressant. Several recent reviews and meta-analyses (Falkai et al 2005(Falkai et al , 2006Moller, 2004 ;Rummel et al 2005Rummel et al , 2006Sepehry et al 2007) found that the weight of available evidence supports the view that SSRI augmentation can improve negative symptoms in chronic schizophrenia patients, but emphasized the need for further research in a broad spectrum of patients particularly as the study of negative symptoms presents considerable difficulties (Murphy et al 2006 ;Sepehry et al 2007 ;Silver, 2008). These include methodological issues such as distinguishing primary and secondary negative symptoms, and uncertainty whether equally effective antidepressants of the SSRI class have similar effectiveness as augmenting agents for negative symptoms.…”

Section: Introductionmentioning

confidence: 99%

The involvement of GABAA receptor in the molecular mechanisms of combined selective serotonin reuptake inhibitor-antipsychotic treatment

Danovich

Weinreb

Youdim³

et al. 2010

Int. J. Neuropsychopharm.

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There is evidence that combining selective serotonin reuptake inhibitor (SSRI) antidepressant and antipsychotic drugs may improve negative symptoms in schizophrenia and resistant symptoms in obsessive-compulsive and affective disorders. To examine the mechanism of action of this treatment we investigated the molecular modulation of γ-aminobutyric acid-A (GABA(A)) receptor components and biochemical pathways associated with GABA(A) receptor function following administration of the SSRI fluvoxamine (Flu) combined with the first-generation antipsychotic haloperidol (Hal) and compared it to the individual drugs and the atypical antipsychotic clozapine (Clz). We analysed prefrontal cortices of Sprague-Dawley rats injected intraperitoneally (i.p.) with the combination of Flu (10 mg/kg) and Hal (1 mg/kg), each drug alone, or Clz (10 mg/kg) after 30 min and 1 h. We found that haloperidol plus fluvoxamine (Hal-Flu) co-administration, and Clz, decreased the level of GABAAβ2/3 receptor subunit in the cytosolic fraction, and increased it in the membrane compartment in rat PFC. Flu or Hal alone did not produce changes in GABAAβ2/3 receptor protein expression. Additionally, Hal-Flu and Clz regulated molecular signalling pathways that modulate GABA(A) receptor function, including protein kinase C (PKC) and extracellular signal-regulated kinase-2 (ERK2). In primary cortical culture, short-term treatment (15 min) with Hal-Flu combination and Clz increased GABAAβ subunit phosphorylation levels. Pretreatment of the cells with PKC inhibitor abolished the effect of the combined treatment, or Clz on phosphorylation of GABA(A) receptor. Inhibition of ERK2 did not alter the effect of drugs on GABA(A) receptor phosphorylation levels. Our findings provide evidence that the combined treatment regulates GABA(A) receptor function and does so via a PKC-dependent pathway.

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“…Recent narrative reviews did not answer these crucial questions and delivered unclear conclusions (1,19,20). Crucially, previous systematic reviews and meta-analyses addressed only specific subgroups of patients with schizophrenia or particular adjunctive medications (cognitive impairment [21], negative symptoms [22][23][24][25], postpsychotic depression [26], add-on noradrenergic and specific serotonergic antidepressants ajp in Advance ajp.psychiatryonline.org 1 …”

mentioning

confidence: 99%

Efficacy and Safety of Antidepressants Added to Antipsychotics for Schizophrenia: A Systematic Review and Meta-Analysis

Helfer

Samara

Huhn³

et al. 2016

AJP

186

116

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Antidepressants for the negative symptoms of schizophrenia

Cited by 32 publications

References 0 publications

Multifunctional Pharmacotherapy: What Can We Learn from Study of Selective Serotonin Reuptake Inhibitor Augmentation of Antipsychotics in Negative-Symptom Schizophrenia?

Multifunctional Pharmacotherapy: What Can We Learn from Study of Selective Serotonin Reuptake Inhibitor Augmentation of Antipsychotics in Negative-Symptom Schizophrenia?

The involvement of GABAA receptor in the molecular mechanisms of combined selective serotonin reuptake inhibitor-antipsychotic treatment

Efficacy and Safety of Antidepressants Added to Antipsychotics for Schizophrenia: A Systematic Review and Meta-Analysis

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