2020-10-21 14:26:49

Prelude

Today’s Topics

  • The neuroscience of psychiatric disorders
  • Major affective (mood) disorders
    • Major Depressive Disorder (depression)
    • Bipolar Disorder

Mental illness lifetime prevalence

Neuroscience of psychiatric disorders

  • Diseases of the mind as 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

Depression

  • 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)

Symptoms, (Mahar, Bambico, Mechawar, & Nobrega, 2014)

Neurobiology of Major Depressive Disorder (MDD)

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

Neurological factors

(Videbech & Ravnkilde, 2004a)

Left Hippocampus

(Videbech & Ravnkilde, 2004b)

Right Hippocampus

Neurological factors

(Fitzgerald et al., 2008)

  1. patients v. controls, (b) patients on SSRIs, (c) patients v. ctrls (happy stim), (d) patients v. controls (sad stim)

Baseline hyperactivity (Hamilton et al., 2012)

Valence-specific hyperactivity (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)

Pharmacological factors

Pharmacological factors

Measuring 5-HT

Treatments for depression

  • Psychotherapy
    • Often effective when combined with drug treatment
  • Exercise
  • Drugs

Drugs

  • Monoamine oxidase (MAO) inhibitors
    • MAO destroys excess monoamines in terminal buttons
    • MAO-I’s boost monoamine levels
  • Tricyclics
    • Inhibit NE, 5-HT reuptake
    • Upregulate monoamine levels, but non-selective = side effects

Drugs

  • 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)

Cymbalta (SNRI)

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
  • Took 6-7 weeks to show response.

Who will benefit from drug therapy?

  • Depends on
    • Early life stress
    • Brain (amygdala) response to emotional faces
  • (Goldstein-Piekarski et al., 2016)
  • Low-stress + low amyg reactivity -> > responding
  • High stress + high amyg reactivity -> > responding

Monoamine hypothesis of depression

  • Disrupted (lowered) levels of monoamines (especially NE & 5-HT) result in depression

Problems with monoamine hypothesis

  • Too simplistic
  • NE, 5-HT 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, & Schene, 2007)

What do drugs do, then?

  • Alter receptor sensitivity?
    • Serotonin presynaptic autoreceptors compensate
    • Postsynaptic upregulation of NE/5-HT effects

What do drugs do, then?

  • 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

Ketamine

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.

Electroconvulsive Therapy (ECT)

Patients speak

Depression’s widespread impact

  • Widespread brain dysfunction
  • Prefrontal cortex, amygdala, HPA axis, circadian rhythms
  • Genetic + environmental factors
  • Disturbance in 5-HT, NE systems, cortisol
  • Many sufferers do not respond to available treatments

Points on depression

  • 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

Bipolar disorder

Bipolar disorder

  • 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, & Tondo, 2006)

Symptoms

Prevalence, subtypes

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

Related symptoms

Genetics

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

Brain responses to emotional faces ≠ depression

(Lawrence et al., 2004)

(Lawrence et al., 2004)

Amyg, Hip volume reduced; ventricles larger

(Hallahan et al., 2011)

Drug treatments

  • Mood stabilizers
    • Lithium (Li)
    • Valproate (Depakote)
  • Anticonvulsants
    • GABA agonists
    • Usually to treat epilepsy
    • e.g. lamotrigine (Lamictal)
  • Atypical antipsychotics

Lithium “discovered” accidentally

  • Injections of manic patients’ urine with lithium compound (chemical stabilizer) into guinea pig test animals
  • Had calming effect
  • John Cade discovered in 1948
  • Earliest effective medications for treating mental illness

Effects of Lithium

  • Reduces mania, minimal effects on depressive states
  • Preserves PFC, hip, amyg volume
  • downregulates DA, glu; upregulates GABA
  • modulates 5-HT, NE
  • levels can be tested/monitored via blood test
  • (Malhi, Tanious, Das, Coulston, & Berk, 2013)

Other treatment options

  • Psychotherapy
  • Electroconvulsive Therapy (ECT)
  • Sleep medications

Prospects

  • STEP-BD cohort (n=1469)
    • 58% achieved recovery
    • 49% had recurrences within 2 years
    • Residual depressive symptoms can persist
  • (Geddes & Miklowitz, 2013)

An Unquiet Mind

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

Next time…

  • Schizophrenia

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