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http://umh1946.edu.umh.es/wp-content/uploads/sites/172/2015/04/Neurocircuitry-of-addiction1.pdf

Neurocircuitry of Addiction

The survival and well-being of all species requires appropriate physiological responses to environmental and homeostatic challenges. The re-establishment and maintenance of homeostasis entails the coordinated activation and control of neuroendocrine and autonomic stress systems. These collective stress responses are mediated by largely overlapping circuits in the limbic forebrain, the hypothalamus and the brainstem, so that the respective contributions of the neuroendocrine and autonomic systems are tuned in accordance with stressor modality and intensity. Limbic regions that are responsible for regulating stress responses intersect with circuits that are responsible for memory and reward, providing a means to tailor the stress response with respect to prior experience and anticipated outcomes.

Neural regulation of endocrine and autonomic stress responses.

OBJECTIVE: Studies of the neurobiological processes underlying drug addiction primarily have focused on limbic subcortical structures. Here the authors evaluated the role of frontal cortical structures in drug addiction. METHOD: An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed. This model and findings from neuroimaging studies on the behavioral, cognitive, and emotional processes that are at the core of drug addiction were used to analyze the involvement of frontal structures in drug addiction. RESULTS: The orbitofrontal cortex and the anterior cingulate gyrus, which are regions neuroanatomically connected with limbic structures, are the frontal cortical areas most frequently implicated in drug addiction. They are activated in addicted subjects during intoxication, craving, and bingeing, and they are deactivated during withdrawal. These regions are also involved in higher-order cognitive and motivational functions, such as the ability to tr...

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Drug Addiction and Its Underlying Neurobiological Basis: Neuroimaging Evidence for the Involvement of the Frontal Cortex

Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems. Each of the four mammalian neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, each neurotrophin activates p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-g1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-kB (NF-kB) and Jun kinase as well as other signalling pathways. Limiting quantities of neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. The neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function. Continued presence of the neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.

/pdf/neurotrophin-regulated-signalling-pathways-30f9o18vav.pdf

Neurotrophin-regulated signalling pathways

Antipsychotics are the first-line agents for managing schizophrenia and related disorders. As with other chronic illnesses, clinicians must often decide whether to switch a patient’s current medication to try to improve treatment response, reduce intolerable side effects and improve quality of life and functioning. Unfortunately, guidance for switching among antipsychotics is lacking, as minimal clinical research on switching strategies exists.

During a switch, patients often experience adverse events that require monitoring. These events are the result of a complex pharmacology in which antipsychotics target various receptor subtypes (e.g., D2, 5-HT2A, M1, α1, H1) with varying degrees of affinity. Often, long-term antagonism of these receptors results in physiologic counter-adaptations, such as receptor upregulation. For example, if a patient switches too quickly from an antipsychotic with high affinity for a given receptor to one with low affinity, rebound and withdrawal symptoms can develop. Conversely, switching too quickly from an antipsychotic with low receptor affinity to one with high affinity can exceed the body’s ability to adapt to the medication and result in receptor-related adverse events. It is recommended that clinicians switch medications gradually to avoid adverse effects. The method (e.g., cross-taper) and duration of switching depend on many variables, including the receptor profile, receptor affinity and the pharmacokinetic parameters of each antipsychotic.1,2 In cases of a significant adverse event, the only option may be to abruptly switch antipsychotics.

Overstimulation of mesolimbic D2 receptors likely contributes to the expression of psychosis. Switching from low- to high-affinity D2 antagonists (e.g., quetiapine to haloperidol) can result in dyskinesias, parkinsonism, akathisia and acute dystonias. In these cases, clinicians should decrease the dose of the high-affinity agent and titrate more slowly. If akathisia persists, β-blockers or benzodiazepines may improve symptoms. Conversely, when switching from high- to low-affinity D2 antagonist, patients may experience breakthrough psychosis, withdrawal dyskinesias and akathisia that may be indistinguishable from agitation. Tapering of the high-affinity agent should be slowed to allow more time for receptor adaptation.

Second-generation antipsychotics also exert their effects in part through the 5-HT2A receptor. When switching from a drug with high affinity for 5-HT2A to one with low affinity (e.g., olanzapine to quetiapine), rebound effects can include agitation, diaphoresis, fever, tremor and confusion. Slow titration over a few weeks should mitigate the occurrence of these adverse events.

Cholinergic M1 receptors control salivation, smooth muscle contractions in the digestive and urinary tracts, memory and cognition. Switching from a low to a high-affinity M1 antagonist (e.g., risperidone to olanzapine) can result in memory and cognitive impairment, dry mouth, constipation and urinary retention. Sugarless, hard candy may alleviate dry mouth, and increasing water and fibre may relieve constipation. Switching from a high- to a low-affinity drug can result in a cholinergic rebound with malaise, nausea, vomiting, diarrhea, sialorrhea, extra-pyramidal symptoms and akathisia. A low-dose anticholinergic may be necessary to control such effects during a switch.

Adrenergic α1 receptors control vascular smooth muscle contraction. Orthostatic hypotension may be a concern when switching from a low- to a high-affinity α1 antagonist (e.g., olanzapine to clozapine). Conversely, switching from a high- to a low-affinity drug may result in rebound hypertension, tachycardia, tremor and restlessness. Blood pressure should be monitored regularly during the switch.

Many antipsychotics block H1 receptors, and switching to a high-affinity drug (e.g., ziprasidone to clozapine) may result in sedation, increased appetite and weight gain. Patients should be informed of these potential effects and the importance of a balanced diet and physical activity. Switching from a high- to a low-affinity H1 blocker may result in insomnia, agitation, anxiety, and akathisia. A sedative and/or anxiolytic may alleviate these effects.

Owing to the diverse receptor profile of antipsychotics, many adverse events may be observed when switching medications. Clinicians should be cautious and closely monitor patients for potential adverse events during the switch. There is a strong need for more clinical research on this topic and for additional resources to help clinicians implement optimal switching strategies to reduce patient discomfort.

https://www.jpn.ca/content/jpn/37/1/E1.full.pdf

Adverse events associated with switching antipsychotics.

The second generation antipsychotic drug risperidone is widely used in the field of child and adolescent psychiatry to treat conditions associated with disruptive behavior, aggression and irritability, such as autism spectrum disorders. While risperidone can provide symptomatic relief for many patients, there is considerable individual variability in the therapeutic response and side-effect profile of the medication. One well established biological factor that contributes to these individual differences is genetic variation in the cytochrome P450 enzyme 2D6. The 2D6 enzyme metabolizes risperidone and therefore affects drug levels and dosing. In the present review, we summarize the current literature on 2D6 variants and their effects on risperidone responses, specifically in children and adolescents. Relevant articles were identified through systematic review, and after irrelevant articles were discarded, ten studies were included in the review. Most prospective studies were well controlled, but often did not have a large enough sample size to make robust statements about rarer variants, including those categorized as ultra-rapid and poor metabolizers. Individual studies demonstrated a role for different genetic variants in risperidone drug efficacy, pharmacokinetics, hyperprolactinemia, weight gain, extrapyramidal symptoms and drug–drug interactions. Where studies overlapped in measurements, there was typically a consensus between results. These findings indicate that the value of 2D6 genotyping in the youth population treated with risperidone requires further study, in particular with the less common variants.

/pdf/a-systematic-review-of-the-effects-of-cyp2d6-phenotypes-on-1gbdxk04vl.pdf

A systematic review of the effects of CYP2D6 phenotypes on risperidone treatment in children and adolescents

Spines, Synapses, and Schizophrenia

Effects of Exercise on Serum Triglycerides and Symptoms of Schizophrenia.

Severe psychotic disorders, which on their own may be a risk factor for metabolic disorder and cardiovascular illness, are clinically compounded by the significant adverse side effects of antipsychotic medications. The majority of patients with severe psychotic disorders (i.e., schizophrenia, bipolar disorder, mania, and depression) must take antipsychotic medications to treat their psychoses and, subsequently, will require efficacious interventions to manage the metabolic consequences of pharmacologic treatment to mitigate excessive mortality associated with cardiovascular illness. We have reviewed the metabolic consequences of antipsychotic treatment and discussed pilot findings from a new nonpharmacologic intervention study looking at the clinical benefits of regular exercise as a management tool for the cardiometabolic risk factors in a cohort with severe mental illness.

/pdf/management-of-medication-related-cardiometabolic-risk-in-2ciod6vym4.pdf

Alasdair M. Barr

Papers

Adverse events associated with switching antipsychotics.

A systematic review of the effects of CYP2D6 phenotypes on risperidone treatment in children and adolescents

Spines, Synapses, and Schizophrenia

Effects of Exercise on Serum Triglycerides and Symptoms of Schizophrenia.

Management of Medication-Related Cardiometabolic Risk in Patients with Severe Mental Illness.