Derek K. Tracy

A systematic review of factors influencing adherence to antipsychotic medication in schizophrenia-spectrum disorders

Adherence to antipsychotics improves outcome in schizophrenia. There is a lack of consensus on which factors most influence adherence behaviour and methodological issues hinder interpretation of existing evidence. A rigorous systematic search designed to identify robustly implicated factors emerging from methodologically rigorous studies narrowed our search to 13 observational studies (total N=6235) relating to adherence, antipsychotics and schizophrenia. Studies varied significantly, with reported adherence rates ranging from 47.2% to 95%. Positive attitude to medication and illness insight were the only factors consistently associated with better adherence, while contradictory results were found for socio-demographic characteristics, symptom severity and side effects. Only distinct aspects of the therapeutic relationship and social support in younger patients were related to good adherence. Antipsychotic type or formulation and neurocognitive functioning did not appear to impact medication adherence. Despite greater methodological rigour in determining studies to include in the present systematic review, it remains difficult to guide clinicians in this vital area and most of the work discussed contained small sample sizes. Future research in this field should therefore prioritise prospective study designs over longer periods and larger samples in naturalistic settings, providing a more appropriate and clinically meaningful framework than widely used cross-sectional designs.

Functional magnetic resonance imaging of inner speech in schizophrenia

BACKGROUND Auditory verbal hallucinations in schizophrenia have been linked to defective monitoring of ones own verbal thoughts. Previous studies have shown that patients with auditory verbal hallucinations show attenuated activation of brain regions involved with auditory processing during the monitoring of inner speech. However, there are no functional magnetic resonance imaging studies explicitly comparing the perception of external speech with internal speech in the same patients with schizophrenia. The present study investigated the functional neuroanatomy of inner and external speech in both patients with schizophrenia and healthy control subjects. METHODS Fifteen patients with schizophrenia and 12 healthy control subjects were studied using functional magnetic resonance imaging while listening to sentences or imagining sentences. RESULTS Significant interactions between group (control subjects vs. patients) and task (listening vs. inner speech) were seen for the left superior temporal gyrus, as well as regions within the cingulate gyrus. CONCLUSIONS Attenuated deactivation of the left superior temporal gyrus in schizophrenia patients during the processing of inner speech may reflect deficits in the forward models subserving self-monitoring.

Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles

Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. This review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. These drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-HT2A receptor, though they also have affinity for other metabotropic serotonin receptors. Hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. They alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory control of sensory input via the thalamus to the cortex. The serotonergic system has long been implicated in anxiety and depressive disorders, and is a major target of most existing antidepressants. Classical hallucinogens alter the functioning of this system, but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time. There is currently an extremely limited but growing literature on hallucinogen safety and clinical application. The drugs appear well tolerated by healthy controls and clinical populations, and the rapid tolerance to repeated administration might reduce the possibility of dependency. Clinical trials reported over the past decade have generally shown positive therapeutic potential, but they are notably few in number. Legislative policy has had a freezing effect on evaluation of these compounds, a better understanding of which might improve our knowledge of the processes involved in consciousness, the neuropathology of depression, and potentially open up new pharmacological therapies.

Dementia praecox redux: A systematic review of the nicotinic receptor as a target for cognitive symptoms of schizophrenia

Most individuals with schizophrenia suffer some cognitive dysfunction: such deficits are predictive of longer-term functioning; and current dopamine-blocking antipsychotics have made little impact on this domain. There is a pressing need to develop novel pharmacological agents to tackle this insidious but most disabling of problems. The acetylcholinergic system is involved in cognitive and attentional processing, and its metabotropic and nicotinic receptors are widespread throughout the brain. Deficits in acetylcholinergic functioning occur in schizophrenia, and high rates of tobacco smoking have been posited to represent a form of self-medication. The nicotinic acetylcholine receptor (nAChR) has emerged as a putative target to improve cognitive deficits in schizophrenia, and this study systematically reviewed the emerging data. Nineteen studies were identified, covering three compound classes: agonists at the α7 and α 4β2 nAChRs, and positive allosteric modulators. Overall data are underwhelming: some studies showed significant improvements in cognition but as many studies had negative findings. It remains unclear if this represents drug limitations or nascent study methodology problems. The literature is particularly hindered by variability in inclusion of smokers, generally small sample sizes, and a lack of consensus on cognitive test batteries. Future work should evaluate longer-term outcomes, and, particularly, the effects of concomitant cognitive training.

Taking the fuel out of the fire: Evidence for the use of anti-inflammatory agents in the treatment of bipolar disorders

BACKGROUND Inflammation has emerged as a potentially important factor - and thus putative pharmacological target - in the pathology of bipolar disorders. However to date no systematic evaluations of the efficacy of add on anti-inflammatory treatment for the depressive and manic episodes have been carried out. METHODS Sixteen articles were ultimately identified - by computer searches of databases (including PsycINFO, MEDLINE, and EMBASE), supplemented by hand searches and personal communication - as meeting study inclusion criteria. RESULTS Anti-manic effects were evaluated in two trials, one of adjunctive n-acetyl cysteine (NAC), one of omega-3 fatty acids (O3FA), and significant improvements only emerged for NAC. Celecoxib had a rapid but short-lived antidepressant effect. Despite limited effects of O3FA on symptoms, imaging data demonstrated alterations in neuronal functioning that might have longer-term therapeutic effects. Evidence was strongest for adjunctive NAC in bipolar depression though conclusions are limited by small sample sizes. LIMITATIONS Definitive conclusions are limited by the paucity of data, small study sizes, and the variability in methodology used. CONCLUSIONS Current evidence for aspirin or celecoxib is insufficient though further investigation of the potential of celecoxib in early illness onset is warranted. Variable evidence exists for add-on O3FA though an indication of short-term treatment effects on membrane fluidity and neuronal activity suggest longer follow-up assessment is needed. The strongest evidence emerged for NAC in depression and future studies must address the role of illness duration and patients׳ baseline medications on outcomes. Careful consideration of lithium toxicity in the elderly and renal impaired is essential.

Sex and schizophrenia: a review of gender differences

Gender differences in schizophrenia have been noted since conceptualisation of the illness. Female onset is typically later, with a second peak post-menopause. Whilst incidence is higher in men, prevalence does not differ. Research has explored possible biopsychosocial causes of these differences. Evidence for genetic and neurodevelopmental factors is weak but support has garnered for the “estrogen hypothesis,” which emphasises the possible neuroprotective effect of estrogen in women. Differences have also been attributed to a differing psychological vulnerability between men and women based on symptomatology: “negative” symptoms are more common in men, whilst “positive” symptoms differ in content between the genders. Social factors might also play a role: whilst women experience more sexual assault, socioeconomic disadvantage and provide more care for dependents, men experience less familial engagement and more environmental hostility. The relevance of gender differences in schizophrenia has meaning beyond academic interest, since they can affect treatment: recent research has, for instance, begun to explore the efficacy of estrogen therapy. The aetiology of gender differences in schizophrenia is only partially understood and more research is needed to elucidate the causal roles of Biopsychosocial factors: understanding these will ultimately improve the treatment of all who suffer from this serious mental illness.

Aging effects on functional auditory and visual processing using fMRI with variable sensory loading

INTRODUCTION Traditionally, studies investigating the functional implications of age-related structural brain alterations have focused on higher cognitive processes; by increasing stimulus load, these studies assess behavioral and neurophysiological performance. In order to understand age-related changes in these higher cognitive processes, it is crucial to examine changes in visual and auditory processes that are the gateways to higher cognitive functions. This study provides evidence for age-related functional decline in visual and auditory processing, and regional alterations in functional brain processing, using non-invasive neuroimaging. METHODS Using functional magnetic resonance imaging (fMRI), younger (n=11; mean age=31) and older (n=10; mean age=68) adults were imaged while observing flashing checkerboard images (passive visual stimuli) and hearing word lists (passive auditory stimuli) across varying stimuli presentation rates. RESULTS Younger adults showed greater overall levels of temporal and occipital cortical activation than older adults for both auditory and visual stimuli. The relative change in activity as a function of stimulus presentation rate showed differences between young and older participants. In visual cortex, the older group showed a decrease in fMRI blood oxygen level dependent (BOLD) signal magnitude as stimulus frequency increased, whereas the younger group showed a linear increase. In auditory cortex, the younger group showed a relative increase as a function of word presentation rate, while older participants showed a relatively stable magnitude of fMRI BOLD response across all rates. When analyzing participants across all ages, only the auditory cortical activation showed a continuous, monotonically decreasing BOLD signal magnitude as a function of age. CONCLUSIONS Our preliminary findings show an age-related decline in demand-related, passive early sensory processing. As stimulus demand increases, visual and auditory cortex do not show increases in activity in older compared to younger people. This may negatively impact on the fidelity of information available to higher cognitive processing. Such evidence may inform future studies focused on cognitive decline in aging.

Examining frontotemporal connectivity and rTMS in healthy controls: Implications for auditory hallucinations in schizophrenia

OBJECTIVE Repetitive transcranial magnetic stimulation (rTMS) has been shown to have clinically beneficial effects in altering the perception of auditory hallucinations (AH) in patients with schizophrenia. However, the mode of action is not clear. Recent neuroimaging findings indicate that rTMS has the potential to induce not only local effects but also changes in remote, functionally connected brain regions. Frontotemporal dysconnectivity has been proposed as a mechanism leading to psychotic symptoms in schizophrenia. The current study examines functional connectivity between temporal and frontal brain regions after rTMS and the implications for AH in schizophrenia. METHOD A connectivity analysis was conducted on the fMRI data of 11 healthy controls receiving rTMS, compared with 11 matched subjects receiving sham TMS, to the temporoparietal junction, before engaging in a task associated with robust frontotemporal activation. RESULTS Compared to the control group, the rTMS group showed an altered frontotemporal connectivity with stronger connectivity between the right temporoparietal cortex and the dorsolateral prefrontal cortex and the angular gyrus. CONCLUSION This finding provides preliminary evidence for the hypothesis that normalizing the functional connectivity between the temporoparietal and frontal brain regions may underlie the therapeutic effect of rTMS on AH in schizophrenia.

Amphetamine sensitization alters reward processing in the human striatum and amygdala.

Dysregulation of mesolimbic dopamine transmission is implicated in a number of psychiatric illnesses characterised by disruption of reward processing and goal-directed behaviour, including schizophrenia, drug addiction and impulse control disorders associated with chronic use of dopamine agonists. Amphetamine sensitization (AS) has been proposed to model the development of this aberrant dopamine signalling and the subsequent dysregulation of incentive motivational processes. However, in humans the effects of AS on the dopamine-sensitive neural circuitry associated with reward processing remains unclear. Here we describe the effects of acute amphetamine administration, following a sensitising dosage regime, on blood oxygen level dependent (BOLD) signal in dopaminoceptive brain regions during a rewarded gambling task performed by healthy volunteers. Using a randomised, double-blind, parallel-groups design, we found clear evidence for sensitization to the subjective effects of the drug, while rewarded reaction times were unchanged. Repeated amphetamine exposure was associated with reduced dorsal striatal BOLD signal during decision making, but enhanced ventromedial caudate activity during reward anticipation. The amygdala BOLD response to reward outcomes was blunted following repeated amphetamine exposure. Positive correlations between subjective sensitization and changes in anticipation- and outcome-related BOLD signal were seen for the caudate nucleus and amygdala, respectively. These data show for the first time in humans that AS changes the functional impact of acute stimulant exposure on the processing of reward-related information within dopaminoceptive regions. Our findings accord with pathophysiological models which implicate aberrant dopaminergic modulation of striatal and amygdala activity in psychosis and drug-related compulsive disorders.

Novel psychoactive substances: types, mechanisms of action, and effects

#### What you need to know In 2016 the Psychoactive Substances Bill banned trading but not possession of all current and future novel psychoactive substances (NPS), sometimes incorrectly called “legal highs,” in an attempt to overcome rapid proliferation of these compounds. Over 560 substances are currently monitored by the European Monitoring Centre for Drugs and Drug Addiction, with 100 new agents identified in 2015 alone. Stimulants and synthetic cannabinoids account for the vast majority and are the types most commonly clinically encountered.1 Online purchases are increasing according to the 2016 Global Drug Survey,2 potentially in response to legislative changes, as is overall NPS use: lifetime consumption was reported by 8% of younger individuals in 2015, up from 5% in 2011, with figures relatively similar between sexes and different countries.3 Professionals report feeling less confident about managing NPS compared with established recreational drugs.4 There were 15 485 accesses to UK National Poisons Information Service TOXBASE relating to “legal highs,” “branded products,” synthetic cannabinoids, and mephedrone in 2014-15.5 Regarding harms from longer term dependence, the UK National Drug Treatment Monitoring System (NDTMS) report in 2015 described 3048 and 1370 adults with documented problematic use of mephedrone and “other” NPS respectively.6 Information on NPS primarily stems from case reports and …