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

ArticleinSchizophrenia Research 147(2-3) · April 2013with58 Reads
DOI: 10.1016/j.schres.2013.03.019 · Source: PubMed
Background: 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. Methods: A systematic search of relevant literature using electronic databases, reference lists, and data presented at recent meetings was conducted. Results: 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. Conclusion: Large, controlled clinical trials to further characterize effects of psychostimulants on NSS in carefully selected patients are warranted.
    • "Also the addition of oestrogens and selective estrogen receptor modulators (SERMs) may hold some promise, although side effects may limit its use (Heringa et al., 2015). The literature suggests that stimulants (DA agonists) such as methylphenidate, amphetamine, and modafinil or armodafinil may improve negative symptoms without worsening of positive symptoms in patients who are stable and treated with effective antipsychotic medications, but the studies lack the rigorous designs required in order to draw firm conclusions (Lindenmayer et al., 2013 ). Several studies are underway using alpha-7 nicotinic receptor (partial) agonists like bradanicline or encenicline in addition to antipsychotics, targeting cognitive and negative symptoms (Deutsch et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Negative symptoms, e.g. social withdrawal, reduced initiative, anhedonia and affective flattening, are notoriously difficult to treat. In this review, we take stock of recent research into treatment of negative symptoms by summarizing psychosocial as well as pharmacological and other biological treatment strategies. Major psychosocial approaches concern social skills training, cognitive behavior therapy for psychosis, cognitive remediation and family intervention. Some positive findings have been reported, with the most robust improvements observed for social skills training. Although cognitive behavior therapy shows significant effects for negative symptoms as a secondary outcome measure, there is a lack of data to allow for definite conclusions of its effectiveness for patients with predominant negative symptoms. With regard to pharmacological interventions, antipsychotics have been shown to improve negative symptoms, but this seems to be limited to secondary negative symptoms in acute patients. It has also been suggested that antipsychotics may aggravate negative symptoms. Recent studies have investigated glutamatergic compounds, e.g. glycine receptor inhibitors and drugs that target the NMDA receptor or metabotropic glutamate 2/3 (mGlu2/3) receptor, but no consistent evidence of improvement of negative symptoms was found. Finally, some small studies have suggested improvement of negative symptoms after non-invasive electromagnetic neurostimulation, but this has only been partly replicated and it is still unclear whether these are robust improvements. We address methodological issues, in particular the heterogeneity of negative symptoms and treatment response, and suggest avenues for future research. There is a need for more detailed studies that focus on different dimensions of negative symptoms.
    Full-text · Article · Jun 2016
    • "Collectively, this line of investigation has established that such agents can be used safely in individuals with psychosis. A review in 2013 specific to negative symptoms concluded evidence supports larger trials be done [33], although a more recent meta-analysis confined to modafanil/armodafanil reported only a small effect size [34] Anticonvulsants Anticonvulsants are frequently used in schizophrenia and it is in this context that a potential effect on negative symptoms has been reported "
    [Show abstract] [Hide abstract] ABSTRACT: Opinion Statement Interest in the negative symptoms of schizophrenia has increased rapidly over the last several decades, paralleling a growing interest in functional, in addition to clinical, recovery, and evidence underscoring the importance negative symptoms play in the former. Efforts continue to better define and measure negative symptoms, distinguish their impact from that of other symptom domains, and establish effective treatments as well as trials to assess these. Multiple interventions have been the subject of investigation, to date, including numerous pharmacological strategies, brain stimulation, and non-somatic approaches. Level and quality of evidence vary considerably, but to this point, no specific treatment can be recommended. This is particularly problematic for individuals burdened with negative symptoms in the face of mild or absent positive symptoms. Presently, clinicians will sometimes turn to interventions that are seen as more “benign” and in line with routine clinical practice. Strategies include use of atypical antipsychotics, ensuring the lowest possible antipsychotic dose that maintains control of positive symptoms (this can involve a shift from antipsychotic polypharmacy to monotherapy), possibly an antidepressant trial (given diagnostic uncertainty and the frequent use of these drugs in schizophrenia), and non-somatic interventions (e.g., cognitive behavioral therapy, CBT). The array and diversity of strategies currently under investigation highlight the lack of evidence-based treatments and our limited understanding regarding negative symptoms underlying etiology and pathophysiology. Their onset, which can precede the first psychotic break, also means that treatments are delayed. From this perspective, identification of biomarkers and/or endophenotypes permitting earlier diagnosis and intervention may serve to improve treatment efficacy as well as outcomes.
    Full-text · Article · Apr 2016
    • "Interestingly, modafinil treatment was associated with a significant reduction in negative symptom ratings without improving or worsening positive symptoms or psychopathology ratings in acute ill schizophrenic patients [16]. Thus, used as adjuvants, DA agonists like modafinil, may improve negative symptoms in patients that are stable and under antipsychotic treatment [14]. Methylphenidate (MPH) is a psychostimulant approved for the pharmacological treatment of medical conditions such as narcolepsy and attention deficit hyperactivity disorder (ADHD). "
    [Show abstract] [Hide abstract] ABSTRACT: In this review we describe how highly addictive psychostimulants such as cocaine and methamphetamine actions might underlie hypoexcitabilty in frontal cortical areas observed in clinical and preclinical models of psychostimulant abuse. We discuss new mechanisms that describe how increments on synaptic dopamine release are linked to reduce calcium influx in both pre and postsynaptic compartments on medial PFC networks, therefore modulating synaptic integration and information. Sustained DA neuromodulation by addictive psychostimulants can “lock” frontal cortical networks in deficient states. On the other hand, other psychostimulants such as modafinil and methylphenidate are considered pharmacological neuroenhancement agents that are popular among healthy people seeking neuroenhancement. More clinical and preclinical research is needed to further clarify mechanisms of actions and physiological effects of cognitive enhancers which show an opposite pattern compared to chronic effect of addictive psychostimulants: they appear to increase cortical excitability. In conclusion, studies summarized here suggest that there is frontal cortex hypoactivity and deficient inhibitory control in drug-addicted individuals. Thus, additional research on physiological effects of cognitive enhancers like modafinil and methylphenidate seems necessary in order to expand current knowledge on mechanisms behind their therapeutic role in the treatment of addiction and other neuropsychiatric disorders.
    Full-text · Article · Jan 2016
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