Pharmacological Treatment of Cognitive Deficits in Nondementing Mental Health Disorders Trevor W
Total Page：16
File Type：pdf, Size：1020Kb
Original article Pharmacological treatment of cognitive deficits in nondementing mental health disorders Trevor W. Robbins, PhD Evidence for pharmacological remediation of cognitive deficits in three major psychiatric disorders—attention deficit- hyperactivity disorder (ADHD), schizophrenia, and depression—is reviewed. ADHD is effectively treated with the stimulant medications methylphenidate and d-amphetamine, as well as nonstimulants such as atomoxetine, implicating cognitive enhancing effects mediated by noradrenaline and dopamine. However, the precise mechanisms underlying these effects remains unclear. Cognitive deficits in schizophrenia are less effectively treated, but attempts via a variety of neurotransmitter strategies are surveyed. The possibility of treating cognitive deficits in depression via antidepressant medication (eg, selective serotonin reuptake inhibitors) and by adjunctive drug treatment has only recently received attention because of confounding, or possibly interactive, effects on mood. Prospects for future advances in this important area may need to take into account transdiagnostic perspectives on cognition (including neurodegenerative diseases) as well as improvements in neuropsychological, neurobiological, and clinical trial design approaches to cognitive enhancement. © 2019, AICH – Servier Group Dialogues Clin Neurosci. 2019;21(3):301-308. doi:10.31887/DCNS.2019.21.3/trobbins Keywords: cognition; memory; attention; ADHD; schizophrenia; depression; dopamine; noradrenaline; serotonin; glutamate; GABA Introduction these and their neural basis, and identifying possible pharma- cological treatments for them, have been important research This important topic can be considered with either a narrow objectives, it must also be admitted that there have been rather or broad focus. If, for example, the position is taken that most few clinical successes to date. psychiatric symptoms can be understood as impairments of cognition, or of cognition interacting with emotional or moti- The search for new cognitive treatments may be aided by vational factors (ie, so-called “hot” cognition), then we would recognizing apparently similar cognitive dysfunctions in be discussing the whole remit of pharmacological treatment what otherwise appear to be very different neuropsychi- in psychiatry. If on the other hand, we consider specifically atric phenotypes. In other words, a memory or attentional the deficits in “cold” cognition, for example, memory and impairment in schizophrenia could possibly be treated with attention, that accompany such diagnoses as schizophrenia a similar medication as in attention deficit-hyperactivity and depression and most other neuropsychiatric disorders, disorder (ADHD). This strategy accepts that the enormous then we are dealing with a much narrower spectrum. Whilst capacity for comorbidity in psychiatry may also extend to it is now acknowledged that cognitive dysfunctions play a the cognitive dimensions. Such considerations mean that the major role in mental health disorders, and that describing treatment of cognitive impairments associated with neuro- Author affiliations: Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. Address for corre- spondence: Dept of Psychology, Downing St, Cambridge CB23EB, UK. (email: [email protected]) Copyright AICH © 2019 – Servier Group. All rights reserved. www.dialogues-cns.org DIALOGUES IN CLINICAL NEUROSCIENCE • Vol 21 • No. 3 • 2019 • 301 Original article Pharmacological remediation of cognitive deficits - Robbins degenerative diseases that are not generally considered as Attention deficit-hyperactivity disorder “mental health disorders” may also be germane. Neuro- degenerative disorders such as Alzheimer disease, Lewy ADHD in either juveniles or adults is generally thought to body disease, and frontotemporal dementia have deficits exemplify so-called “executive” deficits in cognition, which in major, although somewhat distinct, comprise such components as working areas of cognition as their defining memory and planning, cognitive control characteristics, although they are not Many psychiatric (including inhibitory response control usually defined as mental health disor- disorders such as and cognitive flexibility)—although ders. Parkinson disease and Huntington autism exhibit some authors consider that the impair- disease, although classically categorized ments extend to broader domains such as movement disorders, of course show impairments in social as other aspects of memory.1 Classi- clinically significant impairments in the cognition that are core cally, ADHD also presents with major domains of affect and cognition. It can impairments of sustained attention and hardly be claimed that pharmacological to the disorder and distractibility, which have been demon- treatment of cognitive disorders in these may require novel strated to be related to loss of prefrontal conditions has also yet been crowned gray matter, not only in individuals with with success, but this experience may neurobiological ADHD, but also in their first-degree also prove to be informative. In this initiatives and relatives, suggesting a neurobehavioral review, I will focus initially on the status methodological endophenotype of the disorder.2 ADHD is of well-established pharmacological generally considered to be one of the few treatments for cognitive impairments in approaches success stories in treatment in psychiatry. ADHD before considering the present, The more severe forms of this disorder less clear, status of treatment for cogni- are generally treated, apparently para- tive deficits in schizophrenia and depression. I will also doxically, with stimulant drugs such as methylphenidate be considering some future prospects for treating cogni- or d-amphetamine, which boost catecholamine function tion with pharmacological agents in these disorders. Table (ie, dopamine [DA] and noradrenaline [NA]) partially as a I provides a “roadmap” for this brief survey, indicating consequence of their blockade of the DA and NA transporters. the main drugs used for treating cognition in these three Other nonstimulant drugs affecting primarily noradrenergic psychiatric disorders (only a few of which are licensed), function are also employed; such as atomoxetine and guanfa- and incidentally illustrating the diversity and wide range of cine. Meta-analyses indicate that the stimulants exert respect- mechanisms of these compounds. able (medium to large) effect sizes on reducing symptoms ADHD SCHIZOPHRENIA DEPRESSION Methylphenidate D-cycloserine Vortioxetine Amphetamine AMPA-R agonists Modafinil Atomoxetine Memantine Guanfacine Donepezil Bupropion Alpha7 nicotinic agonists Modafinil Amphetamine Modafinil Table I. Drugs used in the treatment of cognitive dysfunction in three psychiatric disorders. ADHD, attention deficit- hyperactivity disorder; AMPA-R, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. 302 • DIALOGUES IN CLINICAL NEUROSCIENCE • Vol 21 • No. 3 • 2019 Original article Pharmacological remediation of cognitive deficits - Robbins in both juvenile3 and adult4 ADHD. Nonstimulants such as mance on laboratory tests of working memory, sustained atomoxetine, bupropion, and guanfacine are also effective, attention, and inhibitory response control (thus ameliorating although with relatively smaller effect sizes. Some analyses impulsivity) in both juveniles and adults with ADHD.12 suggest that amphetamine is also more effective than meth- On the other hand, it has also been reported that although, ylphenidate, perhaps because of its DA-releasing action.5 A for example, decision-making cognition may be rendered large recent meta-analysis6 based on teachers’ and clinicians’ less “risky” by methylphenidate, the drug may also fail to ratings as the main outcome measures largely confirmed the improve adjustment of risk in the face of changing contin- earlier results, the main recommendation being to employ gencies.13 This makes it clear that the concept of a general methylphenidate in children with ADHD and amphetamine “cognitive enhancer” may be inappropriate; cognitive in adult ADHD. These impressive effects are mitigated to benefits may also be accompanied by cognitive costs. This some extent by tolerability and side effects of these drugs and consideration is also relevant to the well-known inverted the (presently largely unsupported) fear of possible stimulant U-shaped function that often determines effects of drugs drug-use disorder. on cognition—in its simplest form that optimal effects may be obtained by intermediate dose. However, it may also However, there is also some evidence that long-term treatment be the case that different behavioral and cognitive tasks with stimulants can have a protective effect against the devel- require different doses for optimal effects. Evidence for this opment of psychiatric disorders such as depression, disruptive comes from studies of the effects of L-Dopa on cognition behavior, or anxiety, and there was less likelihood of repeating in Parkinson’s disease; functions such as spatial working the same school grade.7 Such effects would suggest some memory and cognitive flexibility may be improved but at improvement in academic performance following stimulant the cost of risky decision making and impaired reversal.14,15 medication, however, this is controversial. In a controlled For ADHD, Sprague and Sleator16 showed that a family study, Elia et al8 found that both d-amphetamine and methyl-