Hippocampal Dysfunction in Schizophrenia and Aberrant Hippocampal Synaptic Plasticity in Rodent Model Psychosis: a Selective Review

Schizophrenia is a complex, heterogeneous psychiatric disorder that affects about 1% of the global population. Hippocampal dysfunction has been linked to both cognitive deficits and positive symptoms in schizophrenia. Here, we briefly review current findings on disrupted hippocampal processing from a clinical perspective before concentrating on preclinical studies of aberrant hippocampal synaptic plasticity using the N-methyl-D-aspartate receptor hypofunction model of psychosis and related findings from genetic models. Taken together, the results put the case for maladaptive hippocampal synaptic plasticity and its extrinsic connections as mechanistic underpinnings of cognitive impairments in schizophrenia.

Hallucinations and Phenomenal Consciousness

This chapter examines whether hallucinations are related to the problem of phenomenal consciousness and how historical contributions to the phenomenology of hallucinations, notably the Early Heidelberg School (1909–1932), shed light on hallucinations in schizophrenia. We focus specifically on Mayer-Gross, who in his phenomenological analysis of hallucinations during psychosis, drew from studies conducted with colleagues in Heidelberg: 1. Hypnagogic experiences (i.e., between waking and sleep); 2. Mescaline as a model-psychosis in the 1920’s with particular relationship to the self-disturbances; 3. Detailed accounts by persons with schizophrenia. In heated debates with colleagues (Berze, Jaspers, C. Schneider, Schröder, Specht, Wernicke) Mayer-Gross concluded that hallucinations in schizophrenia may be considered part of the self-disturbances (later contributing to K. Schneider’s First Rank Symptoms). Shifts in the organization of consciousness play a role. However, hallucinations develop from non-conscious low-level sensory anomalies and a disrupted perception action cycle. The chapter concludes with an assessment of how the Early Heidelberg School contributes to today’s phenomenology of hallucinations.

Serotonergic hallucinogens as translational models relevant to schizophrenia

One of the oldest models of schizophrenia is based on the effects of serotonergic hallucinogens such as mescaline, psilocybin, and (+)-lysergic acid diethylamide (LSD), which act through the serotonin 5-HT2A receptor. These compounds produce a ‘model psychosis’ in normal individuals that resembles at least some of the positive symptoms of schizophrenia. Based on these similarities, and because evidence has emerged that the serotonergic system plays a role in the pathogenesis of schizophrenia in some patients, animal models relevant to schizophrenia have been developed based on hallucinogen effects. Here we review the behavioural effects of hallucinogens in four of those models, the receptor and neurochemical mechanisms for the effects and their translational relevance. Despite the difficulty of modelling hallucinogen effects in nonverbal species, animal models of schizophrenia based on hallucinogens have yielded important insights into the linkage between 5-HT and schizophrenia and have helped to identify receptor targets and interactions that could be exploited in the development of new therapeutic agents.

Psychomimesis: LSD and Disability Immersion Experiences of Schizophrenia

<p>Before LSD became infamous as a psychedelic in the late 1960s, it had an earlier career as a psychotomimetic--a drug which could produce a &ldquo;model psychosis&rdquo; or &ldquo;artificial schizophrenia.&rdquo;&nbsp; This paper focuses on the use of LSD in psychiatry in this often overshadowed period.&nbsp; I examine experiments that use LSD as a prosthetic tool to produce &ldquo;disability immersion&rdquo; experiences of schizophrenia in people without psychiatric symptoms or diagnoses.&nbsp; This use of LSD reversed the traditional way drugs circulate in psychiatry: instead of patients receiving mind-altering medication to ameliorate disabling psychiatric symptoms, mental health professionals took LSD to temporarily disable their normal cognition. Despite the problematic nature of disability immersion experiences in general and the negative valence often attached to mental illness in these accounts, these trips into madness produced, I will argue, positive therapeutic insights, perhaps best illustrated by architect Kiyo Izumi&rsquo;s LSD-inspired design for Yorkton Psychiatric Centre.</p><p>Keywords: schizophrenia, mental illness, psychiatry, disability simulation, LSD</p>

Flashback: Psychiatric Experimentation with LSD in Historical Perspective

In the popular mind, d-lysergic acid diethylamide (LSD) research in psychiatry has long been associated with the CIA-funded experiments conducted by Ewen Cameron at the Allen Memorial Institute in Montreal, Quebec. Despite this reputation, a host of medical researchers in the post–World War II era explored LSD for its potential therapeutic value. Some of the most widespread trials in the Western world occurred in Saskatchewan, under the direction of psychiatrists Humphry Osmond (in Weyburn) and Abram Hoffer (in Saskatoon). These medical researchers were first drawn to LSD because of its ability to produce a “model psychosis.” Their experiments with the drug that Osmond was to famously describe as a “psychedelic” led them to hypothesize and promote the biochemical nature of schizophrenia. This brief paper examines the early trials in Saskatchewan, drawing on hospital records, interviews with former research subjects, and the private papers of Hoffer and Osmond. It demonstrates that, far from being fringe medical research, these LSD trials represented a fruitful, and indeed encouraging, branch of psychiatric research occurring alongside more famous and successful trials of the first generation of psychopharmacological agents, such as chlropromazine and imipramine. Ultimately, these LSD experiments failed for 2 reasons, one scientific and the other cultural. First, in the 1950s and early 1960s, the scientific parameters of clinical trials shifted to necessitate randomized controlled trials, which the Saskatchewan researchers had failed to construct. Second, as LSD became increasingly associated with student riots, antiwar demonstrations, and the counterculture, governments intervened to criminalize the drug, restricting and then terminating formal medical research into its potential therapeutic effects.