Scientific progress in understanding human disease can be measured by the effectiveness of its treatment. Antipsychotic drugs have been proven to alleviate acute psychotic symptoms and prevent their ...recurrence in schizophrenia, but the outcomes of most patients historically have been suboptimal. However, a series of findings in studies of first-episode schizophrenia patients transformed the psychiatric field’s thinking about the pathophysiology, course, and potential for disease-modifying effects of treatment. These include the relationship between the duration of untreated psychotic symptoms and outcome; the superior responses of first-episode patients to antipsychotics compared with patients with chronic illness, and the reduction in brain gray matter volume over the course of the illness. Studies of the effectiveness of early detection and intervention models of care have provided encouraging but inconclusive results in limiting the morbidity and modifying the course of illness. Nevertheless, first-episode psychosis studies have established an evidentiary basis for considering a team-based, coordinated specialty approach as the standard of care for treating early psychosis, which has led to their global proliferation. In contrast, while clinical high-risk research has developed an evidence-based care model for decreasing the burden of attenuated symptoms, no treatment has been shown to reduce risk or prevent the transition to syndromal psychosis. Moreover, the current diagnostic criteria for clinical high risk lack adequate specificity for clinical application. What limits our ability to realize the potential of early detection and intervention models of care are the lack of sensitive and specific diagnostic criteria for pre-syndromal schizophrenia, validated biomarkers, and proven therapeutic strategies. Future research requires methodologically rigorous studies in large patient samples, across multiple sites, that ideally are guided by scientifically credible pathophysiological theories for which there is compelling evidence. These caveats notwithstanding, we can reasonably expect future studies to build on the research of the past four decades to advance our knowledge and enable this game-changing model of care to become a reality.
In
The Doors of Perception
, Aldous Huxley described his trial of mescaline as “the most extraordinary and significant experience available to human beings this side of the Beatific Vision.” His ...exegesis was preceded by the synthesis of the hallucinogen lysergic acid diethylamide (LSD) by Sandoz chemist Albert Hoffman in 1938 and was followed by Hoffman’s extraction of psilocybin from
Psilocybe mexicana
in 1959.
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The convergence of scientific research and natural substances historically used by Indigenous peoples in healing and religious rituals sparked interest in what the British psychiatrist Sir Humphrey Osmond termed psychedelic (Greek for “mind manifesting”) drugs. Excitement over . . .
Psychotic Disorders Lieberman, Jeffrey A; First, Michael B
The New England journal of medicine,
07/2018, Letnik:
379, Številka:
3
Journal Article
Recenzirano
Psychosis is a syndrome embedded in several disorders, including schizophrenia and bipolar disorder with psychotic features. Dopamine and glutamate are implicated in the pathophysiology of psychotic ...symptoms. Psychosocial treatments supplement pharmacologic therapy.
The muscarinic receptor agonist xanomeline has antipsychotic properties without dopamine blockade. Cholinergic adverse events limit its use. When xanomeline was combined with trospium to limit ...peripheral effects, scores were better on measures of schizophrenia than were scores with placebo over a period of 5 weeks.
The hippocampus in schizophrenia is characterized by both hypermetabolism and reduced size. It remains unknown whether these abnormalities are mechanistically linked. Here we addressed this question ...by using MRI tools that can map hippocampal metabolism and structure in patients and mouse models. In at-risk patients, hypermetabolism was found to begin in CA1 and spread to the subiculum after psychosis onset. CA1 hypermetabolism at baseline predicted hippocampal atrophy, which occurred during progression to psychosis, most prominently in similar regions. Next, we used ketamine to model conditions of acute psychosis in mice. Acute ketamine reproduced a similar regional pattern of hypermetabolism, while repeated exposure shifted the hippocampus to a hypermetabolic basal state with concurrent atrophy and pathology in parvalbumin-expressing interneurons. Parallel in vivo experiments using the glutamate-reducing drug LY379268 and direct measurements of extracellular glutamate showed that glutamate drives both neuroimaging abnormalities. These findings show that hippocampal hypermetabolism leads to atrophy in psychotic disorder and suggest glutamate as a pathogenic driver.
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► In psychotic disorder and a mouse model, hippocampal hypermetabolism predicts atrophy ► The longitudinal pattern of hypermetabolism and atrophy overlap and spread ► Excess extracellular glutamate drives hypermetabolism and leads to hippocampal interneuronal pathology and atrophy ► Regulating glutamate release in the model prevents hypermetabolism and atrophy
Schobel et al. use functional and structural MRI in individuals at high risk for psychosis to show that hippocampal hypermetabolism predicts hippocampal atrophy across progression to first episode psychosis. A rodent model shows that alterations in extracellular glutamate may contribute to these abnormalities.
Concerns have been raised that treatment with antipsychotic medication might adversely affect long-term outcomes for people with schizophrenia. The evidence cited for these concerns includes the ...association of antipsychotic treatment with brain volume reduction and with dopamine receptor sensitization, which might make patients vulnerable to relapse and illness progression. An international group of experts was convened to examine findings from clinical and basic research relevant to these concerns. Little evidence was found to support a negative long-term effect of initial or maintenance antipsychotic treatment on outcomes, compared with withholding treatment. Randomized controlled trials strongly support the efficacy of antipsychotics for the acute treatment of psychosis and prevention of relapse; correlational evidence suggests that early intervention and reduced duration of untreated psychosis might improve longer-term outcomes. Strategies for treatment discontinuation or alternative nonpharmacologic treatment approaches may benefit a subgroup of patients but may be associated with incremental risk of relapse and require further study, including the development of biomarkers that will enable a precision medicine approach to individualized treatment.
OBJECTIVE: The duration of untreated psychosis may influence response to treatment, reflecting a potentially malleable progressive pathological process. The authors reviewed the literature on the ...association of duration of untreated psychosis with symptom severity at first treatment contact and with treatment outcomes and conducted a meta-analysis examining these relationships. METHOD: English-language articles on duration of untreated psychosis published in peer-reviewed journals through July 2004 were reviewed. Studies that quantitatively assessed the duration of untreated psychosis; identified study subjects who met the criteria for nonaffective psychotic disorders at or close to first treatment; employed cross-sectional analyses of duration of untreated psychosis and of baseline symptoms, neurocognition, brain morphology, or functional measures or prospectively analyzed symptom change, response, or relapse; assessed psychopathology with clinician-rated instruments; and reported subjects' diagnoses (a total of 43 publications from 28 sites) were included in the meta-analysis. RESULTS: Shorter duration of untreated psychosis was associated with greater response to antipsychotic treatment, as measured by severity of global psychopathology, positive symptoms, negative symptoms, and functional outcomes. At the time of treatment initiation, duration of initially untreated psychosis was associated with the severity of negative symptoms but not with the severity of positive symptoms, general psychopathology, or neurocognitive function. CONCLUSIONS: Duration of untreated psychosis may be a potentially modifiable prognostic factor. Understanding the mechanism by which duration of untreated psychosis influences prognosis may lead to better understanding of the pathophysiology of schizophrenia and to improved treatment strategies.
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