A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: Challenges and therapeutic opportunities

New York University School of Medicine, 600 East 125th Street, New York, NY 10035, USA. Electronic address: .
Schizophrenia Research (Impact Factor: 3.92). 04/2013; 147(2-3). DOI: 10.1016/j.schres.2013.03.019
Source: PubMed


Primary negative symptoms of schizophrenia (NSS) contribute heavily to functional disability and treatment of these symptoms continues to be a major unmet need even when the positive (psychotic) symptoms are controlled. The modified dopamine (DA) hypothesis posits that positive symptoms are associated with increased DA activity in the mesolimbic tract whereas NSS and cognitive symptoms are associated with decreased DA activity in the mesocortical (frontal) region. Several studies have reported improvement in NSS with DA agonist use, but with varying degrees of risk for triggering psychotic symptoms, especially in the absence of concurrent antipsychotic drug treatment. This article aims to examine older and newer evidence suggesting that psychostimulants may have a potential therapeutic role in the treatment of NSS together with a thorough review of the potential risks and benefits of psychostimulant administration in individuals with schizophrenia.

A systematic search of relevant literature using electronic databases, reference lists, and data presented at recent meetings was conducted.

Improvement of NSS after psychostimulant administration is reviewed both in challenge and treatment paradigms with various agents such as methylphenidate, amphetamine, and modafinil or armodafinil. The literature points to evidence that, used adjunctively, DA agonists may improve NSS without worsening of positive symptoms in selected patients who are stable and treated with effective antipsychotic medications. Several areas of inadequate study and limitations are identified including small study samples, single-site trials, varying rigor of bias control, the dose and the duration of adjunctive psychostimulant administration, and the potential for development of tolerance.

Large, controlled clinical trials to further characterize effects of psychostimulants on NSS in carefully selected patients are warranted.

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    • "Schizophrenia is a lifelong neurodevelopmental disorder attributed to complex genetic factors and neuropathology (Bakhshi and Chance, 2015; Watkins and Andrews, 2015). Therefore, the onset of schizophrenia may be an interplay of patients' underlying pathophysiology diathesis and environment , rather than simply the trigger of MPH use (Lindenmayer et al., 2013). As expected, we found that older age was associated with a higher risk of developing psychotic disorders (Park et al., 2014). "
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    ABSTRACT: This study estimated the risk of developing psychotic disorders by comparing children with ADHD to non-ADHD controls, and to examine whether methylphenidate (MPH) treatment influences the risks of psychotic disorders. A nationwide cohort of patients who were newly diagnosed with ADHD (n=73,049) and age- and gender-matched controls (n=73,049) were selected from Taiwan's National Health Insurance database from January 2000 to December 2011. All participants were observed until December 31, 2011. Cox regression models were used to estimate the effects of ADHD diagnosis and MPH use on subsequent outcomes. Having a diagnosis of any psychotic disorder and of schizophrenia were set as two different outcomes and were analyzed separately. Compared to the control group, the ADHD group showed significantly increased risk of developing any psychotic disorder (adjusted hazard ratio [aHR], 5.20; 95% confidence interval [CI], 4.30-6.30) and schizophrenia (aHR, 4.65; 95% CI, 3.59-6.04). Compared to ADHD patients without psychosis, patients with ADHD who developed psychosis had significantly older age at first diagnosis of ADHD (9.4±3.3years vs. 10.6±4.0years). Among patients with ADHD, MPH use significantly increased the risk of developing any psychotic disorder (aHR, 1.20; 95% CI, 1.04-1.40), but did not increase the risk of developing schizophrenia (aHR, 1.16; 95% CI, 0.94-1.42). The results indicated that previous diagnoses of ADHD are a powerful indicator of developing psychotic disorders. Nevertheless, the specific mechanisms of the relationships between ADHD, MPH use and psychotic disorders need further elucidation in future clinical studies.
    Schizophrenia Research 09/2015; 168(1). DOI:10.1016/j.schres.2015.08.033 · 3.92 Impact Factor
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    • "Some schizophrenic patients show supersensitivity to indirect DA agonists, and when these drugs are administered in low doses, psychotic symptoms are exacerbated in some patients (for a metaanalysis see [3]). However, some schizophrenics show no response to DA agonists, and there is evidence that DA agonists might actually improve negative symptoms in some schizophrenic patients [57] [58]. Most animal models relevant to schizophrenia also show supersensitivity to direct and indirect DA agonists, as measured by the effects of these drugs on locomotor activity and sensorimotor gating, while a few show subsensitivity to DA agonists [59]. "
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    ABSTRACT: Schizophrenia is thought to be caused, at least in part, by dysfunction in striatal dopamine neurotransmission. Both clinical studies and animal research have implicated the dopamine neuromodulator neurotensin (NT) in the pathophysiology of schizophrenia. Utilizing male mice lacking the NT gene (NT(-/-)), these studies examined the consequences of NT deficiency on dopaminergic tone and function, investigating (1) dopamine concentrations and dopamine receptor and transporter expression and binding in dopaminergic terminal regions, and (2) the behavioral effects of selective dopamine receptor agonists on locomotion and sensorimotor gating in adult NT(-/-) mice compared to wildtype (NT(+/+)) mice. NT(-/-) mice did not differ from NT(+/+) mice in concentrations of dopamine or its metabolite DOPAC in any brain region examined. However, NT(-/-) mice showed significantly increased D1 receptor, D2 receptor, and dopamine transporter (DAT) mRNA in the caudate putamen compared to NT(+/+) controls. NT(-/-) mice also showed elevated D2 receptor binding densities in both the caudate putamen and nucleus accumbens shell compared to NT(+/+) mice. In addition, some of the behavioral effects of the D1-type receptor agonist SKF-82958 and the D2-type receptor agonist quinpirole on locomotion, startle amplitude, and prepulse inhibition were dose-dependently altered in NT(-/-) mice, showing altered D1-type and D2-type receptor sensitivity to stimulation by agonists in the absence of NT. The results indicate that NT deficiency alters striatal dopamine receptor expression, binding, and function. This suggests a critical role for the NT system in the maintenance of striatal DA system homeostasis and implicates NT deficiency in the etiology of dopamine-associated disorders such as schizophrenia. Copyright © 2014. Published by Elsevier B.V.
    Behavioural Brain Research 11/2014; 280. DOI:10.1016/j.bbr.2014.11.014 · 3.03 Impact Factor
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    • "Modafinil increases the levels of dopamine, norepinephrine, and serotonin in the prefrontal cortex (de Saint Hilaire et al., 2001); dopamine levels are also elevated in the nucleus accumbens (Volkow et al., 2009). These actions are mediated through mechanisms such as inhibition of the dopamine transporter (Volkow et al., 2009; Federici et al., 2013) and may underlie possible beneficial mechanisms of ar/mod in the treatment of negative symptoms and cognitive impairment in schizophrenia (Lindenmayer et al., 2013; Scoriels et al., 2013). Benefits in schizophrenia may also accrue through actions on glutamate, gamma amino-butyric acid, and orexin systems (Minzenberg and Carter, 2008). "
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    ABSTRACT: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) of modafinil or armodafinil (ar/mod) augmentation in schizophrenia. We searched PubMed, clinical trial registries, reference lists, and other sources for parallel group, placebo-controlled RCTs. Our primary outcome variable was the effect of ar/mod on negative symptom outcomes. Eight RCTs (pooled N = 372; median duration, 8 weeks) met our selection criteria. Ar/mod (200 mg/day) significantly attenuated negative symptom ratings (6 RCTs; N = 322; standardized mean difference [SMD], -0.26; 95% CI, -0.48 to -0.04). This finding remained similar in all but one sensitivity analysis - when the only RCT in acutely ill patients was excluded, the outcome was no longer statistically significant (SMD, -0.17; 95% CI, -0.51 to 0.06). The absolute advantage for ar/mod was small: just 0.27 points on the PANSS-N (6 RCTs). Ar/mod attenuated total psychopathology ratings (7 RCTs; N = 342; SMD, -0.23; 95% CI, -0.45 to -0.02) but did not influence positive symptom ratings (5 RCTs; N = 302; mean difference, -0.58; 95% CI, -1.71 to 0.55). Although data were limited, cognition, fatigue, daytime drowsiness, adverse events, and drop out rates did not differ significantly between ar/mod and placebo groups. Fixed and random effects models yielded similar results. There was no heterogeneity in all but one analysis. Publication bias could not be tested. We conclude that ar/mod (200 mg/day) is safe and well tolerated in the short-term treatment of schizophrenia. Ar/mod reduces negative symptoms with a small effect size; the absolute advantage is also small, and the advantage disappears when chronically ill patients or those with high negative symptom burden are treated. Ar/mod does not benefit or worsen other symptom dimensions in schizophrenia.
    Journal of Psychiatric Research 09/2014; 60. DOI:10.1016/j.jpsychires.2014.09.013 · 3.96 Impact Factor
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