Topic 11 Psychopathology

Background

Serious Mental Illness among Adults in the Past Year

https://www.samhsa.gov/data/report/2019-nsduh-annual-national-report

Figure 11.1: https://www.samhsa.gov/data/report/2019-nsduh-annual-national-report

More recent data at https://www.samhsa.gov/data/report/2021-nsduh-annual-national-report, but no time series chart that I could find.

Source: https://www.nimh.nih.gov/health/statistics/mental-illness

Figure 11.2: Source: https://www.nimh.nih.gov/health/statistics/mental-illness

Neuroscience of psychiatric disorders

  • Diagnosis via behavior & mood not specific “biomarker”
  • Presume diseases of the mind are disorders of the brain
    • System-wide effects; no single or simple cause
  • Heritability
    • proportion of variance in trait accounted for by genetic factors
    • Higher for psychiatric disorders than non-psychiatric diseases
    • Family member with mental illness highest known risk factor

Depression

Major Depressive Disorder

  • Symptoms
    • Unhappy mood, insomnia, lethargy, loss of pleasure, interest, energy
  • Agitation
  • Lasting for several weeks or more
Table 1 from [@mahar_stress_2014](http://doi.org/10.1016/j.neubiorev.2013.11.009)

Figure 11.3: Table 1 from Mahar et al. (2014)

  • Experienced by ~7% Americans in any year
  • Prevalence (up to ~20% lifetime)
    • Females 2-3x males, higher 40+ years of age
  • Heritability (large, 2.5 M Swedish population study)
    • Females 0.49 (twins); 0.51 (non-twin relatives)
    • Males 0.41 (twins); 0.36 (non-twin relatives)
    • Kendler et al. (2018)

Neurobiology of

  • Reduced sizes of brain regions
  • Hypoactivity
  • Pharmacological factors
  • Synaptic dysfunction

Reduced hippocampal volumes

Left hippocampus from [@Videbech2004-sm](http://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.161.11.1957)

Figure 11.4: Left hippocampus from Videbech and Ravnkilde (2004)

Right hippocampus from [@Videbech2004-sm](http://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.161.11.1957)

Figure 11.5: Right hippocampus from Videbech and Ravnkilde (2004)

Table 1 from [@Palazidou2012-je](http://dx.doi.org/10.1093/bmb/lds004)

Figure 11.6: Table 1 from Palazidou (2012)

Disrupted activity Fitzgerald et al. (2008)

  • Hypoactivity in…
    • Frontal and temporal cortex
    • Anterior cingulate
    • Insula
    • Cerebellum
Figure from [@fitzgerald_meta-analytic_2008](http://dx.doi.org/10.1002/hbm.20426). Row (a) patients v. controls, (b) patients on SSRIs, (c) patients v. ctrls (happy stim), (d) patients v. controls (sad stim).

Figure 11.7: Figure from Fitzgerald et al. (2008). Row (a) patients v. controls, (b) patients on SSRIs, (c) patients v. ctrls (happy stim), (d) patients v. controls (sad stim).

  • Hyperactivity Hamilton et al. (2012)
    • At baseline: in pulvinar nucleus of thalamus
    • In response to negative stimuli: amygdala, insula, anterior cingulate
Figure 1 from [@Hamilton2012-iv](https://doi.org/10.1176/appi.ajp.2012.11071105)

Figure 11.8: Figure 1 from Hamilton et al. (2012)

  • Hypoactivity
    • In response to negative stimuli: prefrontal cortex, striatum of basal ganglia
Figure 1 from [@Hamilton2012-iv](https://doi.org/10.1176/appi.ajp.2012.11071105)

Figure 11.9: Figure 1 from Hamilton et al. (2012)

Disrupted connectivity

  • Resting state fMRI (rsFMRI) in \(n=421\) patients with major depressive disorder and \(n=488\) control subjects.
  • Reduced connectivity between orbitofrontal cortex (OFC) and other areas of the brain
  • Increased connectivity between lateral PFC and other brain areas
  • Cheng et al. (2016)
Figure 1 from [@cheng_medial_2016](http://doi.org/10.1093/brain/aww255)

Figure 11.10: Figure 1 from Cheng et al. (2016)

Figure from [@Palazidou2012-je](http://dx.doi.org/10.1093/bmb/lds004)

Figure 11.11: Figure from Palazidou (2012)

Pharmacological factors

Table 2 from [@Palazidou2012-je](http://dx.doi.org/10.1093/bmb/lds004)

Figure 11.12: Table 2 from Palazidou (2012)

Treatments for depression

  • Psychotherapy
    • Often effective when combined with drug treatment
  • Exercise
  • Drugs
    • Monoamine oxidase (MAO) inhibitors
      • MAO destroys excess monoamines in terminal buttons & glia
      • MAO-I’s boost monoamine levels
    • Tricyclics
      • Inhibit NE, 5-HT reuptake
      • Upregulate monoamine levels, but non-selective => side effects
    • Selective Serotonin Reuptake Inhibitors (SSRIs)
      • Fluoxetine (Prozac, Paxil, Zoloft)
      • Prolong duration of 5-HT in synaptic cleft
      • Also increase brain steroid production
    • Selective Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

Figure 11.13: Cymbalta commercial from Pries (2009)

How well do the drugs work?

  • STAR*D trial
  • On SSRI for 12-14 weeks. ~1/3 achieved remission; 10-15% showed symptom reduction.
  • If SSRI didn’t work, could switch drugs. ~25% became symptom free.
  • 16% of participants dropped out due to tolerability issues
  • 6-7 weeks to show response
Who benefits from drug therapy?
  • Depends on
    • Early life stress (ELS)
    • Brain (amygdala) response to emotional faces
  • Goldstein-Piekarski et al. (2016)
    • Low ELS + low amyg reactivity > responding
    • High ELS + high amyg reactivity > responding
[@goldstein-piekarski_human_2016](http://doi.org/10.1073/pnas.1606671113)

Figure 11.14: Goldstein-Piekarski et al. (2016)

Monoamine hypothesis of depression

  • Disrupted (lowered) levels of monoamines (especially NE & 5-HT) result in depression
  • Problems with monoamine hypothesis
    • Too simplistic
    • Monoamines interact
    • Drugs fast acting (min), but improvement slow (weeks)

“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, and Schene (2007)

  • What do drugs do, then?
    • Alter receptor sensitivity?
      • 5-HT presynaptic autoreceptors compensate
      • Postsynaptic upregulation of NE/5-HT effects
    • Stimulate neurogenesis?
      • Link to neurotrophin, brain-derived nerve growth factor (BDNF)
      • BDNF boosts neurogenesis
      • SSRIs stimulate growth of new neurons in hippocampus
    • Neurogenesis hypothesis, Mahar et al. (2014)
      • Chronic stress causes neural loss in hipp
      • Chronic stress downregulates 5-HT sensitivity
      • Depression ~ chronic stress
      • Anti-depressants upregulate neurogenesis via 5-HT modulation

“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. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions…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.”

– Moncrieff2022-os

New horizons…

Ketamine
From [Washington Post, 2019-03-06](https://www.washingtonpost.com/health/2019/03/06/biggest-advance-depression-years-fda-approves-novel-treatment-hardest-cases/)

Figure 11.15: From Washington Post, 2019-03-06

  • Ketamine is a selective antagonist of the NMDA receptor, an ionotropic glutamate receptor
  • Relieves depressive symptoms relatively quickly Berman et al. (2000) and Zarate et al. (2006)
  • Boosts synaptic spine formation Li et al. (2010) and reverses effects of induced stress
Electroconvulsive Therapy (ECT)
  • Last line of treatment for drug-resistant depression
  • Electric current delivered to the brain causes 30-60s seizure.
  • ECT usually done in a hospital’s operating or recovery room under general anesthesia
  • Once every 2 - 5 days for a total of 6 - 12 sessions.
  • Remission rates of up to 50.9% Dierckx et al. (2012)
  • Seems to work via
    • Anticonvulsant (block Na+ channel or enhance GABA function) effects
    • Neurotrophic (stimulates neurogenesis) effects
  • ECT more effective than Ketamine? Ekstrand et al. (2021)
Figure 3 from [@Ekstrand2021-cq](http://dx.doi.org/10.1093/ijnp/pyab088)

Figure 11.16: Figure 3 from Ekstrand et al. (2021)

Deep brain stimulation

Figure 11.17: From ucsf2021-db

Depression’s impact

  • Widespread brain dysfunction
  • Prefrontal cortex, amygdala, HPA axis, circadian rhythms
  • Genetic + environmental factors
  • Disturbance in 5-HT, NE systems, cortisol
  • Metabolic pathways Pu et al. (2020)
  • Many sufferers do not respond to available treatments
  • Drug treatments affect neuromodulator NT systems, but
    • Can’t effectively measure NT levels
    • Neuromodulators interact, so many side-effects
  • ‘Monoamine hypothesis’ of depression is at-best incomplete
  • ‘Talk’ therapies can change behavior/mood by creating new/strengthened circuits in other areas
  • Emerging therapies (ketamine, deep brain stimulation) show promise, but…

“Leading biological hypotheses propose that biological changes may underlie major depressive disorder onset and relapse/recurrence. Here, we investigate if there is prospective evidence for biomarkers derived from leading theories. We focus on neuroimaging, gastrointestinal factors, immunology, neurotrophic factors, neurotransmitters, hormones, and oxidative stress….Our search resulted in 67,464 articles…Only cortisol (N=19, OR=1.294, p=0.024) showed a predictive effect on onset/relapse/recurrence of MDD, but not on time until MDD onset/relapse/recurrence. However, this effect disappeared when studies including participants with a baseline clinical diagnosis were removed from the analyses…there is a lack of evidence for leading biological theories for onset and maintenance of depression. Only cortisol was identified as potential predictor for MDD, but results are influenced by the disease state. High-quality (prospective) studies on MDD are needed to disentangle the etiology and maintenance of MDD.”

–Kennis et al. (2020)

Bipolar disorder

Background

  • Formerly “manic depression” or “manic depressive disorder”
  • Alternating mood states
    • Mania or hypomania (milder form)
    • Depression
  • Cycles 3-6 mos in length, but
    • Rapid cycling (weeks or days)
  • Suicide risk 20-60x normal population, Baldessarini, Pompili, and Tondo (2006)
Source: http://www.nimh.nih.gov/health/topics/bipolar-disorder/index.shtml

Figure 11.18: Source: http://www.nimh.nih.gov/health/topics/bipolar-disorder/index.shtml

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

(Neuro)biology of

Genetics

  • Overlap between bipolar disorder and schizophrenia
  • Genes for voltage-gated Ca++ channels
    • Regulate NT, hormone release
    • Gene expression, cell metabolism
  • Craddock and Sklar (2013)

Brain responses to emotional faces ≠ depression

Figure from [@lawrence_subcortical_2004](http://dx.doi.org/10.1016/j.biopsych.2003.11.017)

Figure 11.19: Figure from Lawrence et al. (2004)

Figure from [@lawrence_subcortical_2004](http://dx.doi.org/10.1016/j.biopsych.2003.11.017)

Figure 11.20: Figure from Lawrence et al. (2004)

Figure from [@lawrence_subcortical_2004](http://dx.doi.org/10.1016/j.biopsych.2003.11.017)

Figure 11.21: Figure from Lawrence et al. (2004)

Amygdala, hippocampus volume reduced; ventricles larger

Figure 1 from [@hallahan_structural_2011](http://dx.doi.org/10.1016/j.biopsych.2010.08.029)

Figure 11.22: Figure 1 from Hallahan et al. (2011)

Source: [@hallahan_structural_2011](http://dx.doi.org/10.1016/j.biopsych.2010.08.029)

Figure 11.23: Source: Hallahan et al. (2011)

Drug treatments

  • Anti-depressants not especially effective Sidor and MacQueen (2012)
  • Mood stabilizers
    • Lithium (Li)
    • Valproate (Depakote)
  • Anticonvulsants
    • Typically used to treat epilepsy
    • GABA agonists
    • e.g. lamotrigine (Lamictal)
  • Atypical antipsychotics
Lithium
  • “Discovered” accidentally
    • John Cade discovered in 1948
    • Injections of manic patients’ urine with a lithium compound (chemical stabilizer) into guinea pig test animals
    • Had calming effect
    • Earliest effective medications for treating mental illness
  • Effects of
    • Reduces mania, minimal effects on depressive states
    • Preserves PFC, hipp, amyg volumes
    • Has other ‘neuroprotective’ effects Machado-Vieira, Manji, and Zarate (2009)
    • downregulates DA, glutamate; upregulates GABA
    • modulates 5-HT, NE
    • levels can be tested/monitored via blood test
    • Malhi et al. (2013)

Other treatment options

  • Psychotherapy
  • Electroconvulsive Therapy (ECT)
  • Sleep medications

Prospects

  • STEP-BD cohort (\(n=1,469\))
    • 58% achieved recovery
    • 49% (of recovered) had recurrences within 2 years
    • Residual depressive symptoms can persist
  • Geddes and Miklowitz (2013)

BP summed-up

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

Schizophrenia

Background

Figure 11.24: Neuroslicer (2007)

  • Lifetime prevalence ~ 1/100
  • ~1/3 chronic & severe
  • Onset post-puberty, early adulthood
  • Pervasive disturbance in mood, thinking, movement, action, memory, perception

Figure 11.25: TheMentallight (2010)

Screening (Yale PRIME test)

http://www.schizophrenia.com/sztest/primetest.pdf

  1. I think that I have felt that there are odd or unusual things going on that I can’t explain.
  2. I think that I might be able to predict the future.
  3. I may have felt that there could possibly be something interrupting or controlling my thoughts, feelings, or actions.
  4. I get confused at times whether something I experience or perceive may be real or may be just part of my imagination or dreams.
  5. I have thought that it might be possible that other people can read my mind, or that I can read other’s minds.
  6. I wonder if people may be planning to hurt me or even may be about to hurt me.

Origins of the term

  • Bleuler
    • Coined term “schizophrenia” or “split mind”
    • NOT multiple personality disorder
  • Kraeplin
    • Dementia Praecox and Paraphrenia (1919)
    • Emphasized developmental and hereditary origins

“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
  • Impaired executive function
  • Anhedonia (loss of pleasure)
  • Catatonia (reduced movement)

Cognitive symptoms

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

Biological bases

  • Genetic disposition
  • Brain abnormalities
  • Pharmacological bases
  • Developmental origins

Genetic disposition

## New names:
## • `` -> `...1`
## • `` -> `...2`
category pct_risk
General population 1%
Second-degree relative 2.5%
Parent 3.8%
Sibling 8.7%
Child, 1 parent 12%
Child, 2 parents 30%-40%
Twin, monozygotic 40%-50%
a Data from (Tamminga & Medoff, 2000)
  • But, no single gene…
Figure from [@Johnson2017-bp](http://doi.org/10.1016/j.biopsych.2017.06.033)

Figure 11.26: Figure from Johnson et al. (2017)

  • Genes associated with schizophrenia at higher than chance levels. Johnson et al. (2017)
    • NOTCH4, TNF:
      • Part of major histocompatibility complex (MHC), cell membrane specializations involved in the immune system
    • DRD2 (dopamine D2 receptor), KCNN3 (Ca+ activated K+ channel), GRM3 (metabotropic glutamate receptor)

Brain abnormalities

  • Ventricles larger, esp in males

  • Cause or effect?
Figure from [@Kempton2010-ms](http://doi.org/10.1016/j.schres.2010.03.036). Note that ventricular enlargement increases across time

Figure 11.27: Figure from Kempton et al. (2010). Note that ventricular enlargement increases across time

  • Smaller hippocampus, amygdala, thalamus, nucleus accumbens
    • Related to ventricular enlargement?
    • Early disturbance in brain development?
Figure 1 from [@Van_Erp2015-ne](http://doi.org/10.1038/mp.2015.63)

Figure 11.28: Figure 1 from Erp et al. (2015)

  • Rapid gray matter loss in adolescents?
Figure 2 from [@thompson_mapping_2001](http://dx.doi.org/10.1073/pnas.201243998)

Figure 11.29: Figure 2 from Thompson et al. (2001)

https://www.nature.com/articles/mp2017170/figures/1

Figure 11.30: https://www.nature.com/articles/mp2017170/figures/1

  • Increased white matter loss over age
Figure 2 from [@Kochunov2016-cu](http://doi.org/10.1002/hbm.23336)

Figure 11.31: Figure 2 from Kochunov et al. (2016)

Pharmacological bases

Dopamine hypothesis

  • DA (D2 receptor) antagonists (e.g. chlorpromazine)
    • improve positive symptoms
  • Typical antipsychotics are DA D2 receptor antagonists
  • DA agonists
    • amphetamine, cocaine, L-DOPA
    • mimic or exacerbate symptoms
  • Tardive Dyskinesia a side effect of DA antagonists

Figure 11.32: Dyskinesia (2021)

  • Evidence against DA hypothesis…
    • New, atypical antipsychotics
      • (e.g. Clozapine) INCREASE DA in frontal cortex, affect 5-HT
    • Mixed evidence for high DA metabolite levels in CSF
Glutamate hypothesis
  • Psychomimetic drugs…
    • Phencyclidine (PCP), ketamine
    • NMDA receptor antagonists (NMDA glu + voltage-gated)
  • …can induce schizophrenia-like states
  • Schizophrenia -> underactivation of NMDA receptors?
    • Related to NMDA receptor role in learning, plasticity

Developmental origins

Early life stress increases risk

  • Urban vs. rural living

  • Exposure to infection in utero, other birth complications

  • Levine et al. (2016)

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

  • Debost et al. (2015)

    • Danish cohort (n=1,141,447)
    • Exposure to early life stress…
      • in utero did not increase risk of schizophrenia, but
      • but exposure during infancy (0-2 years) increased risk
    • Increased risk associated with an allele of a cortisol-related gene

Schizophrenia summed up

  • Wide-ranging disturbance of mood, thought, action, perception
  • Often co-morbid with MDD Etchecopar-Etchart et al. (2021).
  • Broad changes in brain structure, function, chemistry, development
  • Dopamine hypothesis -> glutamate hypothesis
  • Genetic (polygenic = multiple genes) risk + environmental factors
  • One disorder or many?

References

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