Stimulants for negative symptoms in schizophrenia

BACKGROUND: The negative symptoms of schizophrenia pose a heavy burden on patients and relatives and represent an unmet therapeutic need. The observed association of negative symptoms with impaired reward system function has stimulated research on prodopaminergic agents as potential adjunctive treatments. METHODS: We conducted a systematic review and meta-analysis of published randomized controlled trials of amphetamine, methylphenidate, modafinil, armodafinil, lisdexamphetamine, L-dopa, levodopa, bromocriptine, cabergoline, quinagolide, lisuride, pergolide, apomorphine, ropinirole, pramipexole, piribedil, and rotigotine augmentation in schizophrenia and schizoaffective disorder...

Objectives: Angiotensin I-converting enzyme (ACE) was initially correlated with schizophrenia (SCZ) in studies showing a correlation of ACE increased enzyme activity with memory impairments. Possible role for ACE in SCZ was also suggested by ACE activity interaction with dopaminergic mechanisms to modulate abnormalities of sensorimotor gating. In addition, we have demonstrated higher ACE activity in blood of SCZ subjects, its implication in cognitive performance in SCZ and its power as a predictor for SCZ diagnosis...

One of the most robust neurochemical abnormalities reported in patients living with schizophrenia is an increase in dopamine (DA) synthesis and release in the dorsal striatum (DS). Importantly, it appears that this increase progresses as a patient transitions from a prodromal stage to the clinical diagnosis of schizophrenia. Here we have recreated this pathophysiology in an animal model by increasing the capacity for DA synthesis preferentially within the DS. To achieve this we administer a genetic construct containing the rate-limiting enzymes in DA synthesis-tyrosine hydroxylase (TH), and GTP cyclohydrolase 1 (GCH1) (packaged within an adeno-associated virus)-into the substantia nigra pars compacta (SNpc) of adolescent animals...

Schizophrenia is a chronic, debilitating neuropsychiatric disorder. Multiple transcriptomic gene expression profiling analysis has been used to identify schizophrenia-associated genes, unravel disease-associated biomarkers, and predict clinical outcomes. We aimed to identify gene expression regulation, underlying pathways, and their roles in schizophrenia pathogenesis. We searched the Gene Expression Omnibus (GEO) database for microarray studies of fibroblasts, lymphoblasts, and post-mortem brains of schizophrenia patients...

The dopamine D2 receptor (DRD2) remains the principal target of antipsychotic drugs used for the management of schizophrenia and other psychotic disorders. This receptor is highly expressed within the basal ganglia, more specifically the striatal caudate nucleus and the nucleus accumbens. The general functions, signaling and behavioral contributions of striatal DRD2 are well understood. However, the study of cortical DRD2 expression and functions has for the most part been restricted to a subset of pyramidal neurons and interneurons (e...

Schizophrenia is, in part, a cognitive illness. There are no approved medications for cognitive impairments associated with schizophrenia (CIAS) and primary negative symptoms. Cholinergic and glutamatergic systems, alpha-7 nicotinic acetylcholine (α-7nACh) and N -methyl-D-aspartate (NMDA) receptors, kynurenic acid (KYNA), and mismatch negativity have been implicated in the pathophysiology of CIAS and negative symptoms. Galantamine is an acetylcholinesterase inhibitor that is also a positive allosteric modulator at the α4β2 and α7nACh receptors...

Schizophrenia is a heterogeneous spectrum disorder often associated with detrimental negative symptoms. In recent years, computational approaches to psychiatry have attracted growing attention. Negative symptoms have shown some overlap with general cognitive impairments and were also linked to impaired motivational processing in brain circuits implementing reward prediction. In this review, we outline how computational approaches may help to provide a better understanding of negative symptoms in terms of the potentially underlying behavioural and biological mechanisms...

BACKGROUND: Psychotic symptoms have been linked to salience abnormalities in the brain reward system, perhaps caused by a dysfunction of the dopamine neurotransmission in striatal regions. Blocking dopamine D2 receptors dampens psychotic symptoms and normalises reward disturbances, but a direct relationship between D2 receptor blockade, normalisation of reward processing and symptom improvement has not yet been demonstrated. The current study examined the association between blockade of D2 receptors in the caudate nucleus, alterations in reward processing and the psychopathology in a longitudinal study of antipsychotic-naïve first-episode schizophrenia patients...

OBJECTIVE: Our aim was to summarize the efficacy and safety of atomoxetine, amphetamines, and methylphenidate in schizophrenia. METHODS: We undertook a systematic review, searching PubMed/Scopus/Clinicaltrials.gov for double-blind, randomized, placebo-controlled studies of psychostimulants or atomoxetine in schizophrenia published up to 1 January 2017. A meta-analysis of outcomes reported in two or more studies is presented. RESULTS: We included 22 studies investigating therapeutic effects of stimulants (k=14) or measuring symptomatic worsening/relapse prediction after stimulant challenge (k=6)...

BACKGROUND: Treatment-resistant schizophrenia patients frequently need to be managed with clozapine. However, noncompliance is in-part due to complaints of sedation, fatigue, and low energy. There is little literature reporting on the effectiveness and safety of using stimulants to treat clozapine-induced sedation. We report three cases of treatment-resistant schizophrenia where methylphenidate was used to address these common side-effects. METHODS: To evaluate the effectiveness and safety of psychostimulants in treatment-resistant schizophrenia, we reviewed 3 extensively documented cases of clozapine-induced sedation treated with methylphenidate for over 2 years, in addition to reviewing the literature on this topic...

Formal thought disorder (FTD) is present in most psychiatric disorders and in some healthy individuals. In this Review, we present a comprehensive, integrative, and multilevel account of what is known about FTD, covering genetic, cellular, and neurotransmitter effects, environmental influences, experimental psychology and neuropsychology, brain imaging, phenomenology, linguistics, and treatment. FTD is a dimensional, phenomenologically defined construct, which can be clinically subdivided into positive versus negative and objective versus subjective symptom clusters...

BACKGROUND: Prefrontal-limbic circuits that form the neural architecture for emotion to influence behavior have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and represent a potentially important target of medication treatment that has not been substantively evaluated. This study tested the effect of the psychostimulant prodrug lisdexamfetamine dimesylate on amygdala activation and connectivity during the emotional bias of response execution and inhibition...

Negative symptoms of schizophrenia are associated with poor functional outcome and place a substantial burden on people with this disorder, their families, and health-care systems. We summarise the evolution of the conceptualisation of negative symptoms, the most important findings, and the remaining open questions. Several studies have shown that negative symptoms might be primary to schizophrenia or secondary to other factors, and that they cluster in the domains of avolition-apathy and expressive deficit...

OBJECTIVE: A considerable body of research links cognitive function to dopaminergic transmission in the prefrontal cortex, but less is known about cognition in relation to striatal dopamine D2/3 receptors in unmedicated patients with psychosis. METHODS: We investigated this association by obtaining PET recordings with the high-affinity D2/3 antagonist ligand [18 F] fallypride in 15 medication-free patients with schizophrenia and 11 healthy controls. On the day of PET scanning, we undertook comprehensive neuropsychological testing and assessment of psychopathology using the Positive and Negative Syndrome Scale (PANSS)...

Candidate pro-cognitive drugs for schizophrenia targeting several neurochemical systems have consistently failed to demonstrate robust efficacy. It remains untested whether concurrent antipsychotic medications exert pharmacodynamic interactions that mitigate pro-cognitive action in patients. We used functional MRI (fMRI) in a randomized, double-blind, placebo-controlled within-subject crossover test of single-dose modafinil effects in 27 medicated schizophrenia patients, interrogating brainstem regions where catecholamine systems arise to innervate the cortex, to link cellular and systems-level models of cognitive control...

Schizophrenia is a severe mental disorder characterised by positive and negative symptoms. Negative symptoms are difficult to treat and there is no specific treatment. In small trials, modafinil has been studied in association with antipsychotic treatment. We present three cases of its use; two have developed positive symptoms and one developed renal impairment. Further studies are needed to assess its usefulness in schizophrenia and safety in this group of patients.

BACKGROUND: Psychostimulants are frequently prescribed off-label for adults with major depressive disorder or bipolar disorder. The frequent and increasing usage of stimulants in mood disorders warrants a careful appraisal of the efficacy of this class of agents. Herein, we aim to estimate the efficacy of psychostimulants in adults with unipolar or bipolar depression. METHODS: The PubMed/Medline database was searched from inception to January 16, 2016 for randomized, placebo-controlled clinical trials investigating the antidepressant efficacy of psychostimulants in the treatment of adults with unipolar or bipolar depression...

Amantadine is frequently used in addition to dopaminergic substances like dopamine agonists or L-Dopa in advanced Parkinson disease (PD). However, adverse effects like hallucinations limit its use. PD patients developing severe psychotic symptoms upon treatment with either dopaminergic substances and/or amantadine need to stop intake of any psychotropic substance. Here, we report the case of a 71-year-old PD patient without previously known cognitive impairment. He presented with drug-induced psychotic symptoms due to changes in his therapeutic regimen (increase in COMT inhibitors, newly introduced MAO B inhibitors)...

BACKGROUND: Cognitive deficits in schizophrenia have major functional impacts. Modafinil is a cognitive enhancer whose effect in healthy volunteers is well-described, but whose effects on the cognitive deficits of schizophrenia appear to be inconsistent. Two possible reasons for this are that cognitive test batteries vary in their sensitivity, or that the phase of illness may be important, with patients early in their illness responding better. METHODS: A double-blind, randomised, placebo-controlled single-dose crossover study of modafinil 200 mg examined this with two cognitive batteries [MATRICS Consensus Cognitive Battery (MCCB) and Cambridge Neuropsychological Test Automated Battery (CANTAB)] in 46 participants with under 3 years' duration of DSM-IV schizophrenia, on stable antipsychotic medication...

Targeted cognitive training (TCT) of auditory processing enhances higher-order cognition in schizophrenia patients. TCT performance gains can be detected after 1 training session. As a prelude to a potential clinical trial, we assessed a pharmacological augmentation of cognitive therapy (PACT) strategy by testing if the psychostimulant, amphetamine, augments TCT gains in auditory processing speed (APS) in schizophrenia patients and healthy subjects (HS). HS and schizophrenia patients were tested in a screening session (test 1), followed by a double-blind crossover design (tests 2-3), comparing placebo vs amphetamine (10 mg; 7 d between tests)...