Neuropsychology of Depression

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Neuropsychology of Depression

• David J. Schretlen, PhD
• The Johns Hopkins University

Charles University 3 October 2008 Praha, Czech
Republic
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Major Depressive Disorder

• Marked sadness or irritability for at least 2
  weeks, along with several physiological changes
• Disturbed sleep, appetite, low energy,
  constipation
• Slowed speech, actions
• Decreased experience of pleasure, sexual desire
• Altered self-attitude, feeling guilty or
  worthless
• Crying, thoughts of death or suicide
• Trouble concentrating and making decisions
• Interferes with work and family relations

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Major Depressive Episode

• Can occur once or repeatedly
• A small percentage have manic episodes
• Expansive mood, heightened activity, euphoria,
  etc.
• These can alternate over brief intervals (mixed
  state)
• Pathogenic overlap, but likely a distinct illness
• Variations in course and features
• Psychosis, melancholia, catatonia, post-partum
  onset
• Anxiety as symptom vs. additional disorder
• Double depression

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Genetics

• Twin studies show heritability of 37
• This is much lower than the heritability of SZ
  (75)
• Partly due to heritable depressive personality
  traits
• Family studies show MDD is not single gene
  disease
• Some chromosomal loci of linkage have been
  replicated
• But none has been replicated in every family study

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• Surveyed gt37,000 individuals from 10 countries
  using the WHO-CIDI (Composite International
  Diagnostic Interview)
• Lifetime prevalence 3.0 (Japan) to 16.9
  (USA)
• Female/male ratio 1.2 (Czech Republic) to 2.5
  (Japan)
• Not married/married 1.1 (Brazil) to 2.5
  (Germany)
• Birth cohort 14-24/45 2.2 (Brazil) to 10.9
  (Japan)

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Age of onset and comorbidity

• Odds of MDD in
• Agoraphobia 16.8
• Gen. anxiety disorder 81.6
• Obsessive-compulsive 52.7
• Panic disorder 43.5
• Post-traumatic stress 9.4
• Simple phobia 10.7
• Soc. anxiety disorder 11.9

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Possible Mechanisms

• Monoamine-deficiency hypothesis depression
  caused by deficiency of serotonin and
  norepinephrine
• Antidepressants block the reuptake of 5-HT and NE
• Good predictive power Almost every compound that
  blocks 5-HT and NE reuptake has antidepressant
  properties
• But studies of plasma, urine CSF have yet to
  identify deficiency

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Possible Mechanisms

• Hypothalamic-pituitary-cortisol hypothesis
  Depression caused by excess cortisol
• Stress causes release of corticotropin-releasing
  hormone (CRH), which stimulates the adrenal
  cortices to secrete cortisol
• Depressed patients have elevated cortisol in
  plasma
• In response to dexamethasone, the normal
  cortisol-suppression is absent in about half of
  severely depressed patients
• Other hypotheses Abnormal or altered
  glutamatergic or GABAergic neurotransmission,
  circadian rhythms, etc.

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Possible Contributions of Neural Circuits

• Orbitofrontal cortex Depressed patients respond
  faster to sad words, more to negative feedback,
  and have smaller volumes
• Anterior cingulate gyrus Show decreased
  metabolism, have smaller volumes, and respond
  faster to sad words
• Dorsolateral prefrontal cortex Show increased
  activation by emotional Stroop, but reduced
  metabolism overall
• Hippocampus Depressed elderly adults shown
  reduced volume findings are mixed in younger
  adults, but more consistent in those with
  recurrent depression

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Neurocognitive Impairment in MDD

• A mood disorder, but it involves cognitive
  dysfunction
• Standard neuropsychological tests used to study
• Severity and pattern of deficits (attention,
  effortful)
• Severity/type of MDD (psychotic, melancholic)
• State vs. trait and phase of episode
• Interactions with age (young vs. old, early- vs.
  late-onset)
• Effects of co-morbid conditions (dementia, MCI)
• Experimental measures have been used to examine
  biases in information processing

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• Conducted meta-analysis of 22 studies of MDD
• 726 patients 795 healthy controls (58 women)
• Mean age 57 years mean education 13 years
• Computed effect sizes (Cohens d) for 75 measures
• Mdn d 0.52 (PIQ, Vocabulary) 67 ranged from
  0.310.97
• 12 of 19 timed measures were above the median 7
  below (n.s.)
• Largest effects for RAVLT, CFT smallest for
  CVLT, PASAT, CFT

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Subtypes of MDD

• Melancholic depression
• Severe anhedonia, psychomotor slowing, diurnal
  variation with mood lowest in morning, early
  awakening, appetite and weight loss, excessive
  guilt
• Is this a distinct subtype or simply severe
  depression?
• Motor as opposed to psychomotor slowing might
  be unique to melancholic MDD (Pier et al, 2004)
• Psychotic depression
• Fairly consistent evidence of greater cognitive
  impairment
• Verbal memory, psychomotor speed, executive
  functioning, etc. Overall, good evidence of
  greater but non-specific impairment

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State vs. Trait Effects

• Cognitive dysfunction is common during acute
  episodes
• Melancholic MDD patients perform significantly
  better on testing in the evening compared to the
  morning (Moffoot et al, 1994)
• Can persist following remission, but evidence is
  inconsistent
• Remitted, drug-free MDD patients show mild
  deficits on selected executive and attention
  tests (Weiland-Fiedler et al, 2004)
• Healthy twins discordant for unipolar depression
  performed poorly across multiple cognitive
  domains (Christensen et al, 2006)
• Memory deficits might be state-dependent, while
  executive and attention deficits might be more
  trait-dependent (Porter et al, 2007)

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Age Interactions

• Greater cognitive impairment is seen in depressed
  patients gt60 than those lt60 years old
  (Christensen et al, 1997)
• Fewer studies have considered age of illness
  onset
• Late-onset (LOD) vs. early-onset (EOD)
  depression
• LOD has lower rate of family history, higher rate
  of dementia, and more white matter
  hyperintensities than EOD
• EOD patients have greater hippocampal volume loss
  than LOD, possibly due to effects of excess
  glucocorticoid effects

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• Meta-analysis of 10 studies of 351 LOD, 174
  EOD, and 413 elderly NCs
• Executive deficits are typical of LOD
• Memory and psychomotor speed deficits are
  common to both

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Depression, MCI, and Dementia

• Disproportionate cerebral ischemia on MRI in
  patients with LOD led to notion of vascular
  depression (Krishnan et al, 1997)
• Co-morbidity of depression and cognitive
  impairment in the elderly Does the denominator
  make a difference?
• Cognitive impairment occurs 2555 (or more) of
  depressed elderly adults (Butters et al, 2000
  Lee et al, 2007 Lockwood et al, 2000)
• Depression occurs in 1050 of community samples
  of adults with MCI (Apostolova Cummings, 2008)
• Depression occurs in 50 or more patients with AD
  (Starkstein Mizrahi, 2006 Lyketsos et al, 2002)

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• Treated 73 elderly adults with major depressive
  disorder
• Tested patients and 21 NCs at baseline, 1, 4,
  6, and 12 weeks
• 32 patients responded to treatment with
  paroxetine (Paxil)
• Rx responders did not improve on any cognitive
  measure

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A Few Words about Treatment
NEJM, 2008
PLoS, 2008
2008
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• Identified 74 clinical trials of 12 drugs
  registered with FDA
• Extracted efficacy data from these double-blind,
  placebo-controlled studies of short term
  treatment of depression
• Recorded FDAs judgment (positive, negative,
  questionable)
• Reviewed published studies identified best
  match
• Categorized trials on basis of FDA regulatory
  decision
• Computed effect size for each trial
• Found that 12,564 patients participated in these
  trials
• Data from 3449 (27) were not published
• Data from 1843 (15) published in contradiction
  to FDAs finding
• Effect sizes smaller for unpublished than
  published studies and for journal than FDA reports

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(2007)

• 7 studies (n 903) 459 psychotherapy vs. 444
  combined
• All studies involved adult patients with MDD
• Mean baseline Hamilton DRS scores 17 (mild) to
  27 (severe)
• 820 weeks treatment 1624 sessions mostly
  cognitive therapy
• Dropout rates did not differ (25 combined 24
  psychotherapy)

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Case S. O.

• 63-year-old, married, retired electrical engineer
• Chief complaint HPI
• Complains of memory failures over past 3-4 years
  forgets church sermons, appointments, telephone
  numbers, chores, family events
• Consulted neurologist, brain MRI showed scattered
  WMH, ? atrophy
• Family history
• Father died of Alzheimer disease at age 88
  mother died of cancer at age 77 patient has no
  siblings, but has 3 adult children, all healthy
• Medical/psychiatric history
• Hypertension, high cholesterol, acid reflux, and
  low mood/anxiety. Medications Lisinopril,
  Crestor, Niaspan, guanfacine, omeprazole,
  aspirin, Lexapro, Trazodone, and vitamins

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Conclusions

• MDD is very prevalent, afflicts more women than
  men, and can emerge at almost any age
• Frequently preceded or accompanied by other
  conditions
• Likely caused by both genetic and non-genetic
  factors, but its pathophysiology remains poorly
  understood
• More evidence points to monoamine deficiency
  and/or HPA abnormalities than other putative
  mechanisms
• Neuroimaging studies suggest that abnormalities
  in several neural structures might play a role in
  MDD

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Conclusions

• Studies show state- and trait-like cognitive
  impairments of mild to moderate severity
• Might vary with age of onset and co-morbid
  illnesses
• Deficits more severe in elderly patients with
  depression
• Executive deficits might be more specific to LOD
  decreased speed and memory are common to both EOD
  and LOD
• Combined treatment better than monotherapy
• However, psychotherapy leads to remission of
  symptoms in up to 50 of individuals with
  mild-moderate MDD