2_Psychosis and the Schizophrenia Spectrum.pdf

Psychosis and the Schizophrenia Spectrum Clinical Description and Epidemiology The idea that THEY were watching me was irrational but persistent. The idea of who exactly THEY were, and why THEY were watching me, was an idea that evolved. My concept of THEM grew and began to color every experienc...

Psychosis and the Schizophrenia Spectrum Clinical Description and Epidemiology The idea that THEY were watching me was irrational but persistent. The idea of who exactly THEY were, and why THEY were watching me, was an idea that evolved. My concept of THEM grew and began to color every experience I had. After a few months, everything that happened to me was somehow related to THEM, or was caused by THEM…. Even as my mental illness worsened, some part of my rational mind was still active. I tried to reconcile my new perception of reality with the reality I had known in earlier years. This new concept of THEM even infiltrated my memories. Experiences I had had years ago were now colored by this new perceptual filter…. I am using the word psychotic to mean that my understanding and perception of the real world diverged sharply from reality. I could no longer work. At one point, I wondered whether my whole existence and everything I experienced was manufactured by a virtual reality machine and whether my whole life was spent in a laboratory run by some type of alien creatures.” – Kurt Snyder on his personal experience with schizophrenia (Snyder, 2006) History of Schizophrenia • Emil Kraeplin credited with detailed clinical description of “dementia praecox” (1896) • “Schizophrenia” coined by Eugen Bleuler in 1911 • From schizo “to split or crack” + phren “mind” • But schizophrenia != split personality – think more “split from reality” • Has been argued that schizophrenia was historically an overly vague category that was deployed as a “catch-all diagnosis” to label and control socially “undesirable” behaviors/people (McNally, 2016) “Thought disorder” is not the whole story • Three main symptom clusters: • Positive (difficulties with “reality testing”; presence of delusions, hallucinations) • Psychosis defined by “loss of contact with reality” • Negative (reductions in motivation, emotion, speech, sociality) • Disorganization (of behavior, speech, cognition) Positive Symptoms: Delusions • “Bizarre” beliefs not aligned with reality • Firmly held even in the presence of apparently disconfirming evidence • Examples of types of delusions • Ideas of reference • Persecutory • Grandiose • Somatic • Feelings or behavior controlled by external force • Strongly influence understanding of self, others, experiences, situations, the world Positive Symptoms: Hallucinations • Perceptual experiences that don’t correspond to external sensory stimuli • Distinct from transient “perceptual illusions” (but on the same continuum?) • Most often auditory, followed by visual • But can be tactile, olfactory, gustatory, somatic – or multimodal • Have “relevance” for the person – that is, people may act on, be emotionally or cognitively affected by their hallucinations • e.g., people who considers themselves to be socially inferior more likely to perceive the voices as more powerful (Paulik, 2011) • May or may not be experienced as disturbing/distressing (“negative voice content”) Negative Symptoms • Diminishments in motivation, pleasure, social closeness, and emotion expression • Have profound effects on the lives of people with schizophrenia • Strong predictor of clinical and functional outcomes, quality of life • Often persist beyond episodes of acute psychosis Examples of Negative Symptoms • Avolition – lack of motivation or goal-directed behavior, apathy • Asociality – lack of interest in being around others, close relationships • Anhedonia – lack of interest or pleasure in rewarding activities • Appears to be about anticipating pleasure (vs. experiencing pleasure) • Blunted affect – lack of outward expression of emotion • Alogia – significant reduction in speech Disorganized Symptoms • Catatonia • Persistent immobility or peculiar, increased, repeated gestures • Less commonly seen today due to increased access to treatment • Disorganized behavior • Difficulty organizing behaviors, conforming to community standards • Disorganized speech • Problems in organizing ideas, speaking coherently • Loose association (derailment) • Difficulty sticking to one topic Other “Schizophrenia Spectrum” Disorders • Schizophreniform Disorder • Same symptoms as schizophrenia • Symptom duration greater than 1 month, but less than 6 months • Symptoms seem to often be triggered by extreme stress (e.g., traumatic bereavement) • Schizoaffective Disorder • Having both psychotic and, separately, mood episodes (depression and/or mania) • Delusional Disorder • Persistent delusions without the other symptoms of schizophrenia Epidemiology of Schizophrenia • Lifetime prevalence ~1% • Seems to affect men slightly more often than women • Evidence of greater severity, earlier average onset in men • Onset typically in late adolescence or early adulthood • Diagnosis of schizophrenia in childhood is rare, controversial • Diagnosed disproportionately in Black Americans vs. White Americans • May reflect clinician bias? Social determinants? Course of Schizophrenia The Prototypical Course The Complex Reality • The premorbid and prodromal periods can look quite different for different people (Schultze-Lutter et al., 2015) • One piece of evidence, among many, that schizophrenia may really be a group of disorders • Presents challenges for early detection and intervention Consequences of Schizophrenia • Considered prototypical “severe and persistent mental illness” (SPMI) • High rates of substance use, unemployment, housing insecurity, incarceration • People with schizophrenia die 15-20 years earlier than others in their cohort (25% attributed to suicide; 10% to accidents; the rest to medical conditions and lack of quality medical care, especially cardiovascular disease; Laursen et al., 2014) • Prognosis is quite varied, though (depending, e.g., on treatment receipt, community support) • Some will only have a single pronounced psychotic episode in their lifetimes • Some experience recurrent psychotic episodes with largely intact psychosocial function between episodes • Others have highly intractable psychotic episodes with notable functional impairment Consequences of Receiving a Schizophrenia Diagnosis “…many of us who have been psychiatrically labeled have received powerful messages from professionals who… tell us that by virtue of our diagnosis the question of our being has already been answered and our futures are already sealed…. I can remember such a time during my third hospitalization. I was 18 years old. I asked the psychiatrist I was working with, What’s wrong with me? He said, You have a disease called chronic schizophrenia…. If you take medications for the rest of your life and avoid stress, then maybe you can cope. And as he spoke these words I could feel the weight of them crushing my already fragile hopes and dreams and aspirations for my life” – Patricia Deegan, PhD Etiological Factors Behavioral Genetics • Highly, but not 100% heritable (estimated h2 ~.80 in twin studies) • Children born to women with schizophrenia raised by adoptive parents without schizophrenia had an 8-10% likelihood of developing schizophrenia • Evidence of overlapping architecture of genetic vulnerability (e.g., with bipolar disorder) • Negative symptoms may have stronger genetic component? Molecular Genetics: “The Missing Heritability” • As with other DSM diagnoses, “candidate genes” not robustly associated with schizophrenia (Johnson et al., 2017) • Massively polygenic • Genetic variants and mutations observed to be associated with risk in GWAS collectively fall far short of fully accounting for heritability observed in twin studies • Only some people with these variants have schizophrenia • These variants are not specific to schizophrenia • Yet another piece of evidence that schizophrenia may really be a family of disorders Neurotransmission: The Dopamine Hypothesis • Early biological theory that schizophrenia was caused by excess levels of dopamine • Dopamine antagonists showed efficacy in treating positive symptoms • Amphetamines (which are dopamine agonists) can induce psychosis • “Aberrant salience” • As with the monoamine theory of depression, though, simple versions of the dopamine hypothesis don’t hold up to scrutiny Toward More Refined Models of Neurotransmission • Revised Dopamine Hypothesis • Excessive presynaptic synthesis of dopamine at D2 receptors? • Some evidence of increased number of D2 and D3 receptors, but may be a result of medication? • More clearly linked to positive and disorganized sx than negative sx • Glutamate Hypothesis • Interactions with dopamine • Still a lot of work to be done! Brain Structure and Function: Enlarged Ventricles • Ventricles = large open structures filled with cerebrospinal fluid • Enlargement suggestive of underdevelopment or atrophy • Correlated with worse: • Performance on neuropsychological tests • Functioning before onset • Response to medication • But not seen in everyone with schizophrenia Brain Structure and Function: Prefrontal Cortex • Plays important role in speech, decision-making, emotion, goaldirected behavior among many other functions • Reduction in gray matter and overall volume • Reduced gray matter volume predicted onset of schizophrenia in a high-risk sample (McGorry) • “Hypofrontality” hypothesis: function of the PFC associated with severity of negative symptoms • Again, important to remember that these findings aren’t universal Brain Structure and Function: The Temporal Cortex • Structural and functional abnormalities in and around the temporal cortex observed in some studies, but findings not consistent (Keshavan et al., 2008) • Reduced hippocampal volume • Also observed in relatives of people with schizophrenia • Again, not specific to schizophrenia (e.g., PTSD) • May be related to stress reactivity and a disrupted HPA axis More on Stress Reactivity • High stress reactivity also found in first-degree relatives • Greater decreases in positive mood and increases in negative mood under stress • Recurrence of psychosis more likely during times of life stress • Cortisol release affects dopamine, glutamate activity • Chronic over-activation of the HPA axis can have neurotoxic consequences (e.g., chronic inflammation) Brain Structure & Function: Connectivity • Loss of dendritic spines in the PFC • Less connectivity in brain white matter in frontal and temporal cortices • Less connectivity between brain networks • Difficulty disengaging the default mode network? (Karlsgodt et al., 2010) • Connectivity seems to be related to genetic vulnerability Brain Structure and Function: Is Schizophrenia a Neurodevelopmental Disorder? • Early environmental influences on neurodevelopment • Brain “insult” during gestation or birth • High rates of delivery complications – may result in reduced oxygen, loss of cortical gray matter • Maternal infection, exposure to toxic chemicals? • Maternal stress • Early malnutrition So why do full-blown symptoms not emerge until adolescence or early adulthood? • Evidence of subtle, earlier emerging differences in motor skills, expression of negative emotion, attention • Ex: Walker’s study of home movies • Prefrontal cortex matures through adolescence and early adulthood • Too much of a typical thing: excessive pruning of synaptic connections? • Dopamine activity peaks in adolescence • Adolescence fraught with stress Early Cannabis Use • Cannabis use during adolescence associated with 2x risk, greater symptom severity • Directionality? • People in the early stages of developing schizophrenia might be more likely to use cannabis • Even after childhood psychotic symptoms considered, cannabis use still a significant predictor (Fergusson et al., 2003) • Mechanisms? • Evidence that THC increases dopamine in several areas of the brain (El Khoury et al., 2012) • Some evidence that cannabis use accelerates schizophrenia-relevant brain changes (Rais et al., 2008) Altered Perceptions & Hallucinations • Global alterations in basic perceptual and attentional processes • Picking out a target syllable amidst distracting background speech • Tracking visual objects smoothly Altered Perceptions & Hallucinations • Bias toward speech detection (e.g., Bristow et al. 2014) • Some evidence that people with auditory hallucinations might produce the nerve signals of sound in their brains, “hear” them, and then believe that external sources are responsible (“source monitoring”)? • More blood flow in Broca’s area (associated with speech production) during hallucinations • Subtle movements of the chin muscles, changes in respiration immediately prior to hearing voices Environmental and Sociocultural Factors • Although schizophrenia is considered by many a prototype of a biological mental illness (“brain disorder”), there’s strong evidence that the environment matters! • Always important to remember that environments/experiences shape the brain/brain development • Poverty: sociogenic or downward drift? • Urbanicity: (air) pollution? • Symptom manifestations (e.g., types of delusions and hallucinations) and course of illness vary across countries • Some evidence that outcomes are better in the Global South (Jablensky) • Outcomes substantially better when people with schizophrenia have stable employment, housing Environmental and Sociocultural Factors • Impact of receiving the diagnostic label – stigma • Self-stigma reduces hope, self-esteem, self-efficacy • Is it time for a name change? (Mesholam-Gately et al., 2021) • Family dynamics do not cause schizophrenia, but can affect risk, course of illness • Combination of genetic risk and adverse environments associated with highest risk (e.g., Wahlberg et al., 1997; Tienari et al., 2004) • OTOH, in the absence of genetic risk, association with family environment is minimal • Familial “expressed emotion” (hostility, criticism, intrusiveness) associated with risk of relapse, re-hospitalization (Butzlaff & Hooley, 1998) – may tie back to stress • Schizophrenia can disrupt family dynamics (e.g., Liem, 1974) Treatment Medication • Often regarded as foundation of treatment, similar to bipolar disorder • Used both to reduce acute symptoms and reduce risk of relapse • Common property: block dopamine D2 receptors • Many also modulate action of 5-HT2 • Disconnect between neurochemistry and symptom improvement (similar to what we see with SSRIs) • Some evidence of improvement can often be seen within 24 hours, but it can take weeks or months for maximal clinical benefit to be achieved • Suggests that the mechanisms of action of our medications may be quite complex – with medication initiating “downstream” changes First-Generation Antipsychotics • Early antipsychotics heralded as wonder drugs, cure-alls • Reduce positive and disorganization symptoms, but little or no effect on negative symptoms • 30+% don’t respond • Pretty miserable side effect profile • History of commonly prescribing waaaaay too high doses, especially in institutional settings Second-Generation “Atypical” Antipsychotics • Efficacy • Equally as effective as first-generation at reducing positive, disorganization symptoms • Maybe modestly more effective at reducing negative symptoms? • Maybe more effective at improving cognitive functioning? • Side effect profile considered less bad, but that may not be saying much Evaluating Medication Treatments • Recent review of acute efficacy of antipsychotics found ~50% had minimal response vs. placebo & only 23% had a strongly positive response (Haddad & Correll, 2018) • Long-term maintenance with antipsychotics effective in reducing relapse and hospitalization, improving functioning and quality of life (Ceraso et al., 2022; Moncrieff et al., 2023) • Valid concerns about long-term effects on the brain (e.g., Ho et al., 2011; Harrow & Jobe, 2018) • High rate of non-use/discontinuation – why? (Roe et al., 2009) • Side effects, coercive nature of treatment, association of treatment initiation with stress of psychotic episode, disorganization, multiple barriers to reliable treatment access, stigma • High rate of relapse following discontinuation • In other words, a lot more work needed to develop more effective medications that people will be more willing to use AND to reimagine healthcare interactions and policies (e.g., shared decision-making) • Some novel medications target systems other than dopamine/serotonin (e.g., KarXT is a muscarinic agonist) Psychological Treatments • Current treatment recommendations indicate that medication should be combined with psychosocial intervention • Examples of evidence-based treatments • Cognitive behavioral therapy for psychosis • Family therapy • Social skills training • Combined treatment associated with: • Lower rates of relapse, treatment discontinuation • Improved functioning, quality of life Final Thoughts • Psychosis features not unique to schizophrenia • Other psychological disorders (e.g., MDD, Bipolar I) • Physical illnesses (e.g., temporal lobe epilepsy) • Substances • Hypnagogic hallucinations • Some studies have estimated that 13-23% of people experience one or more psychotic symptoms sometime during their lives • Increasingly apparent that schizophrenia is not a single disorder • Multiple etiologic pathways to a set of overlapping symptoms • As elsewhere, produces challenges for clinical practice, research Even More Final Thoughts • Schizophrenia is genetically influenced, not genetically determined • Schizophrenia often associated with very significant impairment, but functional recovery by no means impossible! (Eglit et al., 2019) • Early intervention/prevention is important (first-episode psychosis programs) • Effective community programs can facilitate recovery (e.g., ACT teams) • Some of the impairment is probably driven more by social factors (e.g., stigma) than by schizophrenia itself • But fewer than half of the people who need them receive appropriate community mental health services • Shortage of services, lack of funding • Poor coordination of services