Psychopathology I

2025-10-28

Rick Gilmore

Department of Psychology

Prelude

valliseasons (2006)

Today’s topics

  • Announcement
    • Move Quiz 3 to Tuesday, November 11
  • Mental illness & psychiatric disorders
  • Major depressive disorder

Mental illness

Prevalence: Any

“Mental illness” (n.d.)

Prevalence: Serious

“Mental illness” (n.d.)

Neuroscience of

https://medworksmedia.com/rating-scales/the-hamilton-rating-scale-for-depression/

Neuroscience of…

  • No biological test or biomarker
  • System-wide effects; no single or simple cause

Heritability of…

  • proportion of variance in trait accounted for by genetic factors
    • e.g., p(your sibling has X | you have X)
  • Higher for psychiatric disorders than non-psychiatric diseases
  • Family member with mental illness often highest known risk factor

Heritability of…

Pettersson et al. (2019) Figure 1.

Gene & brain measures relate across disorders

Bourque et al. (2024)

Source: Giphy.com

Major depressive disorder

Major Depressive Disorder

  • Symptoms
    • Depressed mood or loss of interest in daily activities
    • Plus 4 others
  • Most of the day, every day, lasting for two weeks or more

Khaliq (2022)

Major Depressive Disorder (MDD)

  • Experienced by ~8% Americans in any year
  • U.S. prevalence up to ~20% lifetime (higher than international average; Bromet et al. (2011))
    • Females 2-3x males
  • Median age of first episode ~25 years

Prevalence of MD episodes

“NSDUH national releases” (n.d.)

“NSDUH national releases” (n.d.)

MDD is a complex disorder that cannot be fully explained by any one single established biological or environmental pathway. Instead, MDD seems to be caused by a combination of genetic, environmental, psychological and biological factors.

– Marx et al. (2023)

Causes & effects

Pathogenesis

Figure 1 from Cui et al. (2024)

Otte et al. (2016) Figure 3.

MDD Heritability

  • Large, 2.5 M Swedish population study, Kendler, Ohlsson, Lichtenstein, Sundquist, & Sundquist (2018)
    • Females 0.49 (twins); 0.51 (non-twin relatives)
    • Males 0.41 (twins); 0.36 (non-twin relatives)
  • ~35% (Geschwind & Flint, 2015; Otte et al., 2016)

Sex-specific genetic effects

Cai (2025) Figure 1 comment on Thomas et al. (2025)

Genes and environment interact

Otte et al. (2016) Figure 4.

Smaller brain areas

Otte et al. (2016) Figure 5.

Monoamine hypothesis

  • Or “chemical imbalance theory”
  • More: euphoria
  • Less: depression

Monoamine hypothesis

Treatments

Drugs

  • Monoamine oxidase (MAO) inhibitors (MAOIs)
  • Tricyclics
  • Selective (Serotonin/Serotonin-Norephinephrine) Reuptake Inhibitors

Monoamine oxidase (MAO) inhibitors

  • MAO degrade monoamines in synaptic cleft (chemical inactivation)
  • MAOI’s boost monoamine levels
  • Used to treat MDD, panic disorder, anxiety disorder
  • But side effects, especially high blood pressure

Tricyclics

  • Named for atomic structure
  • Inhibit NE, 5-HT reuptake -> Upregulate monoamine levels
  • Used to treat MDD, anxiety
  • Non-selective -> side effects

Tricyclics

The long-term effects of tricyclic antidepressants and the effects on quality of life are unknown. Short-term results suggest that tricyclic antidepressants may reduce depressive symptoms while also increasing the risks of serious adverse events, but these results were based on low and very low certainty evidence.

– Kamp et al. (2024)

Selective Serotonin Reuptake Inhibitors (SSRIs)

  • Fluoxetine (Prozac, Paxil, Zoloft)
  • Prolong duration of 5-HT in synaptic cleft
    • Increase brain steroid production
  • Selective Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
    • Inhibit both 5-HT and NE transporters

Cymbalta an SNRI

How well do the drugs work?

  • STAR*D trial
  • $35M NIMH-funded clinical trial 2001-2007, target n=4,000

STAR*D protocol

  • On SSRI for 12-14 weeks.
  • If SSRI didn’t work, could switch drugs up to 3 times

STAR*D results

  • 1st round
    • ~1/3 achieved remission; 10-15% showed symptom reduction
  • 2nd round
    • ~25% became symptom free.
  • 67% cumulative remission rate
  • 6-7 weeks to show response

STAR*D reanalyzed

  • Pigott, Kim, Xu, Kirsch, & Amsterdam (2023)
  • STAR*D investigators deviated from their own protocol (raters were not blind to status)
  • Included data that should have been excluded

In contrast to the STAR*D-reported 67% cumulative remission rate after up to four antidepressant treatment trials, the rate was 35.0% when using the protocol-stipulated HRSD and inclusion in data analysis criteria

Monoamine hypothesis reconsidered

  • Too simplistic
  • Monoamines interact
  • Drugs fast acting (min), but improvement slow (weeks)

Otte et al. (2016) Figure 7.

No correlation between serotonin and its metabolite 5-HIAA in the cerebrospinal fluid and [11C]AZ10419369 binding measured with PET in healthy volunteers.

– Tiger et al. (2015)

…we performed the first meta-analysis of the mood effects in [acute tryptophan depletion] ATD and [alpha-methyl-para-tyrosine] APTD studies. The depletion of monoamine systems (both 5-HT and NE/DA) does not decrease mood in healthy controls. However, in healthy controls with a family history of MDD the results suggest that mood is slightly decreased…by [monoamine depletion]…

– Ruhé, Mason, & Schene (2007)

“*The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research.

– Moncrieff et al. (2022)

The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.

– Moncrieff et al. (2022)

When drugs do work, how?

  • Alter receptor sensitivity?
    • 5-HT terminals contain autoreceptors
    • Presynaptic autoreceptors regulate 5-HT release
    • Autoreceptors compensate for elevated 5-HT from SSRIs
    • Postsynaptic receptor upregulation of NE/5-HT effects?

When drugs do work, how?

  • Stimulate neurogenesis?
    • Link to neurotrophin, brain-derived nerve growth factor (BDNF)
    • BDNF boosts neurogenesis

Neurogenesis hypothesis

  • Mahar, Bambico, Mechawar, & Nobrega (2014)
  • Chronic stress causes neural loss in hippocampus
    • Cortisol and CRF receptors in hippocampus
  • Chronic stress down-regulates 5-HT sensitivity

Neurogenesis hypothesis

  • Depression ~ chronic stress
  • Anti-depressants upregulate neurogenesis via 5-HT modulation
  • Hippocampus one site where neurogenesis occurs in adults

Other approaches

  • Psychotherapy
  • Other drugs
  • Neurostimulation

Psychotherapy

  • Effective in treating MDD
  • No clear differences among therapy types
  • Similar outcomes as antidepressant medication
  • Otte et al. (2016)

Ketamine

  • Selective antagonist of the NMDA receptor
    • NMDA is an ionotropic glutamate (Glu) receptor
  • Relieves depressive symptoms relatively quickly (Berman et al., 2000; Zarate et al., 2006)
  • But only for a short time
  • Boosts synaptic spine formation (Li et al., 2010) and reverses effects of induced stress

Ketamine

Our findings show that ketamine and esketamine may be more efficacious than placebo at 24 hours. How these findings translate into clinical practice, however, is not entirely clear…Long term non‐inferiority RCTs comparing repeated ketamine and esketamine, and rigorous real‐world monitoring are needed to establish comprehensive data on safety and efficacy.

– Dean et al. (2021)

Electroconvulsive Therapy (ECT)

  • Last line of treatment for drug-resistant depression
  • Electric current delivered to the brain causes 30-60s seizure
  • Usually done in a hospital’s operating or recovery room under general anesthesia

Electroconvulsive Therapy (ECT)

  • Once every 2-5 days for a total of 6-12 sessions.
  • Remission rates of up to 50.9% (Dierckx, Heijnen, Broek, & Birkenhäger, 2012)
  • Seems to work via
    • Intrinsic anticonvulsant effects (brain responds to seizure with seizure-preventing responses)
    • Neurotrophic (stimulates neurogenesis) effects

Electroconvulsive Therapy (ECT)

  • ECT more effective than ketamine?

Figure 3 from Ekstrand et al. (2021)

Deep brain stimulation

– (ucsf) (2021)

Other neurostimulation

  • Vagal (Xth cranial) nerve stimulation
  • Parasympathetic branch of ANS
  • Mixed (afferent/efferent)

“Magnetism” (n.d.)

Other neurostimulation

  • Transcranial Magnetic Stimulation
  • Non-invasive
  • Weekday treatments, 20-30 min/session, 4-8 weeks
  • Target dorsolateral prefrontal cortex
  • Kim, PhD, Widge, & PhD (2024)

Jaekl (n.d.)

Wrap-up

Main points

  • MDD highly prevalent
  • MDD widespread dysfunction
  • No universal biomarkers, but high heritability

Main points

  • Weak evidence for “chemical imbalance”
  • Monoamine drugs widely prescribed, work sometimes in some people
  • Weak evidence for monoamine hypothesis
  • How reuptake inhibitors alleviate MDD not clear

Main points

  • Some evidence for altered HPA system, especially cortisol
  • MDD may mimic chronic stress & affect neural development
  • Ketamine faster acting than monoamine-affecting drugs

Main points

  • Psychotherapy can be effective
  • ECT, deep brain stimulation for treatment-resistant depression

…High-quality (prospective) studies on MDD are needed to disentangle the etiology and maintenance of MDD.

– Kennis et al. (2020)

Next time

  • Bipolar disorder and schizophrenia

Resources

About

This talk was produced using Quarto, using the RStudio Integrated Development Environment (IDE), version 2025.9.2.418.

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/

References

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