Psychopathology II

2025-10-30

Rick Gilmore

Department of Psychology

Prelude

– MariahCareyVEVO (2010)

Today’s topics

  • Warm-up
  • Bipolar disorder
  • Schizophrenia

Warm-up

For most psychiatric disorders, diagnostic tests involve behavior not biological measures. True or False?

  • True
  • False

For most psychiatric disorders, diagnostic tests involve behavior not biological measures. True or False?

  • True
  • False

The monoamine hypothesis of depression claims that monoamine levels are ________ in people with major depressive disorder (MDD).

  • A. elevated
  • B. reduced
  • C. variable
  • D. normal

The monoamine hypothesis of depression claims that monoamine levels are ________ in people with major depressive disorder (MDD).

  • A. elevated
  • B. reduced
  • C. variable
  • D. normal

The fast-acting effect of ketamine on MDD undermines the monoamine hypothesis of depression because…

  • A. Drugs that upregulate monoamines take weeks to work.
  • B. Ketamine affects glutamate NMDA receptors.
  • C. SSRIs are selective for norepinephrine.
  • D. Both A. and B.

The fast-acting effect of ketamine on MDD undermines the monoamine hypothesis of depression because…

  • A. Drugs that upregulate monoamines take weeks to work.
  • B. Ketamine affects glutamate NMDA receptors.
  • C. SSRIs are selective for norepinephrine.
  • D. Both A. and B.

Bipolar (BP) disorder

Background on BP

  • Formerly “manic depression” or “manic depressive disorder”
  • Alternating mood states
    • Mania or hypomania (milder form)
    • Depression

Background on BP

Source: NIMH

Background on BP

  • 1-3% lifetime prevalence, subthreshold affects another ~2% Merikangas et al. (2007)
  • Subtypes
    • Bipolar I: manic episodes, possible depressive ones
    • Bipolar II: no manic episodes but hypomania (disinhibition, irritability/agitation) + depression

Background on BP

  • Psychosis (hallucinations or delusions)
  • Anxiety, attention-deficit hyperactivity disorder (ADHD)
  • Substance abuse

(Neuro)biology of BP

Bourque et al. (2024)

Genetics of BP

  • 40-70% concordance (higher in some samples)
  • Polygenic (many risk alleles)
  • BP and schizophrenia overlap (Craddock & Sklar, 2013)

Pettersson et al. (2019) Figure 1.

Brain activation changes

  • Areas linked to…
    • cognitive control \(\downarrow\)
    • emotion regulation \(\uparrow\)

Maletic & Raison (2014). Figure 2.

Brain structure

  • Volume
    • Amygdala, hippocampus, thalamus \(\downarrow\)
    • ventricles \(\uparrow\)

Ching et al. (2022) Figure 4a.

Brain structure

Ching et al. (2022) Figure 5.

  • Cerebral cortex thinner
    • BP vs. healthy controls (a)
    • BP on anti-convulsant (c)
  • But, thicker for BP on Li (b)

Brain structure

  • White matter altered.

Ching et al. (2022) Figure 7

Toward a unified model

Magioncalda & Martino (2022) Figure 2.

Therapies for BP

  • Psychotherapy
  • Electroconvulsive Therapy (ECT)
  • Sleep medications
  • Drugs

Drugs

  • Anti-depressants not especially effective (Gitlin, 2018; Sidor & MacQueen, 2012)
    • May destablize mood
  • Anticonvulsants
    • Typically used to treat epilepsy
    • Usually GABA-A receptor agonists
    • e.g. lamotrigine (Lamictal)
  • Atypical antipsychotics

Drugs

  • Mood stabilizers

Lithium (Li)

  • “Discovered” accidentally in 1948
  • John Cade
    • Injected manic patients’ urine with a lithium compound (chemical stabilizer) into guinea pig test animals
    • Had calming effect
  • Earliest effective medication for treating mental illness

Wikipedia

Li effects

  • Malhi, Tanious, Das, Coulston, & Berk (2013)
  • Reduces mania, minimal effects on depressive states
  • Preserves volume of prefrontal cortex (PFC), hippocampus, amygdala
  • downregulates DA, glutamate; upregulates GABA
  • levels can be tested/monitored via blood test

Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) cohort

ENIGMA BD working group

Bi, Che, & Bai (2022). Figure 1. Major challenges facing neuroimaging studies of BD and how the ENIGMA BD Working Group meets these challenges

BP summed-up

  • Changes in mood, but ≠ depression
  • Genetic + environmental risk
  • Changes in emotion processing, cognition, size of hippocampus
  • Heterogeneous
  • No simple link to a specific NT system

From a neurobiological perspective there is no such thing as bipolar disorder. Rather, it is almost certainly the case that many somewhat similar, but subtly different, pathological conditions produce a disease state that we currently diagnose as bipolarity…

– Maletic & Raison (2014)

From a neurobiological perspective there is no such thing as bipolar disorder. Rather, it is almost certainly the case that many somewhat similar, but subtly different, pathological conditions produce a disease state that we currently diagnose as bipolarity…

– Maletic & Raison (2014)

This heterogeneity – reflected in the lack of synergy between our current diagnostic schema and our rapidly advancing scientific understanding of the condition – limits attempts to articulate an integrated perspective on bipolar disorder.

– Maletic & Raison (2014)

Schizophrenia (SCZ)

– Neuroslicer (2007)

Background on SCZ

  • Lifetime prevalence ~ 0.3-0.7%
    • Broader definitions suggest 2-3 or 3-5%
  • ~1/3 chronic & severe
  • Onset post-puberty, early adulthood

Background on SCZ

  • Males: Earlier onset & greater severity
  • Pervasive disturbance in mood, thinking, movement, action, memory, perception
  • Increased (early) mortality

“Positive” symptoms

  • “Additions” to behavior
  • Disordered thought
  • Delusions of grandeur, persecution
  • Hallucinations (usually auditory)
  • Bizarre behavior

“Negative” symptoms

  • “Reductions” in behavior
  • Poverty of speech
  • Flat affect
  • Social withdrawal
  • Anhedonia (loss of pleasure)
  • Catatonia (reduced movement)

Cognitive symptoms

  • Memory
  • Attention
  • Planning, decision-making
  • Social cognition
  • Movement

Affective symptoms

  • Depressive, manic states

Os & Kapur (2009). Figure 2.

Biological bases

  • Genetic predisposition
  • Brain abnormalities
  • Neurochemical factors
  • Developmental origins

Genetic predisposition

  • Heritability >50%

Pettersson et al. (2019) Figure 1.

Genetic risk

Johnson et al. (2017)

Brain structure

  • Ventricles larger, esp in males

Suddath, Christison, Torrey, Casanova, & Weinberger (1990)

Ventricle size

  • Increases across time
  • Especially in the more impaired

Davis et al. (1998)

(Davis et al., 1998)

Kempton, Stahl, Williams, & DeLisi (2010)

Brain structure

  • Hippocampus, amygdala, thalamus, nucleus accumbens (NAc; ventral striatum) smaller
  • Related to ventricular enlargement?
  • Early disturbance in brain development?

Erp et al. (2015).

White matter disruption

Kelly et al. (2017)

White matter loss over age

Kochunov et al. (2016)

Disruptions heterogenous

Compared to the healthy comparison group, the schizophrenia group showed widespread reductions in FA and CT, involving virtually all white matter tracts and cortical regions. Paradoxically, however, no more than 15–20% of patients deviated from the normative range for any single tract or region…Thus, while infra-normal deviations were common among patients, their anatomical loci were highly inconsistent between individuals.

– Lv et al. (2021)

Neurochemical factors

  • Dopamine (DA) hypothesis
  • Glutamate (Glu) hypothesis

Dopamine (DA) hypothesis

Evidence for…

  • DA (\(D_2\) receptor) antagonists (e.g. chlorpromazine)
    • improve positive symptoms
  • Typical antipsychotics are DA \(D_2\) receptor antagonists
  • DA agonists (amphetamine, cocaine, L-DOPA)
    • mimic or exacerbate symptoms

Evidence against…

  • New, atypical antipsychotics
    • (e.g. Clozapine) increase DA in frontal cortex, affect 5-HT
  • Mixed evidence for high DA metabolite levels in CSF
  • Some DA neurons may release 5-HT, cannabinoids, glutamate (Seutin, 2005)

Glutamate hypothesis

  • Psychomimetic drugs
    • Phencyclidine (PCP)
    • Ketamine
  • Can induce schizophrenia-like states

Ketamine

  • dissociative (secondary) anesthetic
  • side effects
    • hallucinations, blurred vision, delirium, floating sensations, vivid dreams

Sleigh, Harvey, Voss, & Denny (2014)

Ketamine

  • Primarily a glutamate NMDA receptor (NMDA-R) antagonist1
  • Affects other systems (Sleigh et al., 2014)

Sleigh et al. (2014)

Glutamate hypothesis

  • Schizophrenia \(\rightarrow\) underactivation of NMDA receptors?
    • Note: NMDA-R role in learning, plasticity
  • NMDA-R antagonists \(\rightarrow\) neurodegeneration, excitotoxicity, & apoptosis

The data show that the disorder (SCZ) is characterized by lower levels of glutamate, GABA and dopamine in the frontal cortex, and potentially other cortical regions; higher levels of glutamate in the basal ganglia and thalamus; and greater dopamine synthesis and release capacity in the basal ganglia relative to healthy individuals. Moreover, connections among some of these alterations indicate a key role for fronto-thalamo-striatal–midbrain circuits in the pathophysiology of the disorder.

— Howes, Bukala, & Beck (2023)

Developmental origins

  • Gray matter loss in adolescence
  • Early life stress

Developmental origins

  • Rapid gray matter loss in adolescents in adolescents with early onset SCZ

Thompson et al. (2001)

Early life stressors

Early life stress

  • Levine, Levav, Pugachova, Yoffe, & Becher (2016)
    • Children (N=51,233) of parents who born during Nazi era (1922-1945)
    • Emigrated before (indirect exposure) or after (direct exposure) Nazi era
    • Children exposed to direct stress in utero or postnatally
      • Did not differ in rates of schizophrenia, but
      • Had higher re-hospitalization rates

Early life stress

  • Danish cohort (n=1,141,447), Debost et al. (2015)
    • Exposure to early life stress
      • in utero did not increase risk of schizophrenia, but
      • stress during 0-2 years increased risk
    • Increased risk associated with cortisol-related gene

Summing up SCZ

  • Wide-ranging disturbance of mood, thought, action, perception
  • Broad changes in brain structure, function, chemistry, development
  • (Simplistic) dopamine hypothesis giving way to signalling network (DA + Glu + GABA) models
  • Genetic (polygenic = multiple genes) risk + environmental factors

Howes et al. (2023) Figure 4

Howes et al. (2023) Figure 2

Novel approaches

Wrap up

Main points

  • BP and SCZ separable, but related
  • Reduced brain volume, thickness, connectivity
  • Mood stabilizers (e.g., Li) + psychotherapy often effective BP treatments
  • Can measure Li via blood test, but not Glu, DA, GABA
  • DA hypothesis of SCZ \(\rightarrow\) glutamate hypothesis

Next time

  • No class on Tuesday, November 4, 2025. Election Day
  • Thursday, November 6, 2025
    • Emotion

Resources

About

This talk was produced using Quarto, using the RStudio Integrated Development Environment (IDE), version r Sys.getenv("RSTUDIO_VER").

The source files are in R and R Markdown, then rendered to HTML using the revealJS framework. The HTML slides are hosted in a GitHub repo and served by GitHub pages: https://psu-psychology.github.io/psych-260-2025-fall/

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