Neuropsychiatric Disorders
Schizophrenia
Affective Disorders
Anxiety Disorders
SCHIZOPHRENIA
Symptoms
– Positive: i.e., noted by presence
(dissociative, illogical thought, delusions,
hallucinations)
– Negative: i.e., noted by absence
(social withdrawal, blunted affect, poverty of
thought/speech)
Prevalence
– 1% of population
– universal disorder, i.e. all races and cultures
Study Objective #1
SCHIZOPHRENIA
Heritability and Genetic Factors
– Family Studies
increased risk with family history
– Twin Studies
concordance rates of monozygotic vs.
dizygotic twins
– Adoption Studies
biological vs. adoptive parents
Study Objective #2
SCHIZOPHRENIA
Study Objective #2
SCHIZOPHRENIA
Causes?
– Multiple causes
– Several genes implicated in vulnerability
to schizophrenia
– Multiple experiential factors possible
contributors
e.g., infections, autoimmune reactions,
toxins, traumatic injury, stress
ANTIPSYCHOTIC DRUGS
Discovery of Chlorpromazine – 1950s
– Laborit examined phenothiazines to prevent
post-surgical shock
Reserpine
– derived from snake root plant in India
– antischizophrenic effects, but causes severe
hypotension
Haloperidol
– Butyrophenone
– D2 dopamine antagonist
Atypical Neuroleptics
– e.g., clozapine, risperidone
Study Objective #6
ANTIPSYCHOTIC DRUGS
Side Effects of Classical Neuroleptics
Parkinsonian features
Tardive Dyskinesia
Atypical Antipsychotics
Do not produce motor side effects
Some evidence that clozapine may improve or
reverse TD symptoms
Clozapine and agranulocytosis
Study Objective #10
ANTIPSYCHOTIC DRUGS
Receptor Binding Affinities of a Variety of
Antipsychotic Drugs
DOPAMINE HYPOTHESIS
Early clues to the dopamine link to
schizophrenia:
– Parkinsonian side effects of the first
antipsychotic drugs (1950s)
– Clinical observations of amphetamineinduced psychosis (1960s)
– Discoveries of antipsychotic drug receptor
pharmacology (1970s)
Study Objectives #5 and #7
DOPAMINE HYPOTHESIS
Criticisms of the DA hypothesis:
– Delayed onset of therapeutic effects relative to the
pharmacological effects:
slow developing compensatory change, such as DA cell
depolarization block may account for therapeutic effects
– Normal levels of DA metabolites are present in CSF of
many schizophrenics.
– Results of postmortem and PET studies of D2 receptor
density are inconsistent. (Pinel fails to address this.)
– Atypical Antipsychotic Drugs (e.g., clozapine, risperidol)
have relatively low D2 binding affinities, and greater affinity
for D1, D3, or D4 receptors as well as 5-HT receptors.
Study Objectives #8 and #9
GLUTAMATE INVOLVEMENT
– PCP models of psychosis
Chronic PCP produces negative symptoms and reduces
metabolic activity in prefrontal cortex.
PCP blocks NMDA glutamate receptors.
– NMDA receptor hypofunction hypothesis
NMDA receptor hypofunction causes excessive
glutamate release which triggers neuronal injury
throughout corticolimbic regions.
This might account for negative symptoms and the
cognitive deterioration associated with schizophrenia.
PCP RECEPTOR
Effects of PCP
Model of PCP receptor
HYPOFRONTALITY HYPOTHESIS
Hypofrontality: reduced frontal lobe activity
– Functional imaging techniques (fMRI, PET, SPECT)
reveal decreased metabolic activity in frontal cortex of
schizophrenics.
– Difficult cognitive tasks that increase frontal lobe
activity in normal controls fail to do so in
schizophrenics.
e.g., Wisconsin Card Sorting Task
– PCP produces hypofrontality in nonhuman primates,
and this effect is reversed by antipsychotic drugs.
Study Objective #4
NEUROPATHOLOGY OF
SCHIZOPHRENIA
Enlarged cerebral ventricles and reduced
cortical volume (signs of tissue atrophy)
– Tissue loss most evident in prefrontal, cingulate,
and medial temporal cortex
Study Objective #3
SCHIZOPHRENIA
– Limbic system abnormalities
Hippocampus: disoriented pyramidal cells
Parahippocampal and entorhinal cortex
Cingulate Cortex
AFFECTIVE DISORDERS
Categories
– Bipolar Affective Disorder
– Unipolar Affective Disorder
Reactive Depression (clearly triggered by
environmental event)
Endogenous Depression (no obvious
environmental cause)
DEPRESSION
Symptoms
– mood changes, lost interest, energy and appetite,
concentration difficulties, restless agitation
Prevalence
– 5% males, 8% females
Heritability
– Twin studies 70% concordance in mz vs. 20% in dz
twins
– Adoption studies: higher rates in biological vs foster
parents
Study Objective #11
DEPRESSION AND SUICIDE
~ 80% of suicide victims depressed
Research has shown
– lower 5-HT levels in suicide attempters.
– higher cortisol levels in suicide attempters.
Some evidence for genetic anomalies in
suicidal individuals
– e.g., A variant version of gene for 5-HT2A
receptor is more common in suicide victims
vs. controls.
DEPRESSION: Treatments
Treatments
– Pharmacological treatments
– REM deprivation
– Electroconvulsive Therapy (ECT)
limited to severe cases
Study Objective #16
ANTIDEPRESSANT DRUGS
serendipitous discoveries
MAOIs
– Iproniazid in tuberculosis treatment, 1950s
– potential side effects: hypertensive crisis with
tyramine rich foods
Tricyclics
– Imipramine first tested as an antipsychotic
Lithium
– John Cade’s discoveries in experiments with
guinea pigs
SSRIs and SNRIs
Study Objective #17
ANTIDEPRESSANT DRUGS
mechanisms of action
Study Objective #17
DEPRESSION: Neural Mechanisms
Monoamine Theory
– Decreased 5-HT/NE activity
– Main support: efficacy of pharmacological treatments
i.e., monoaminergic actions of antidepressants
– Criticisms:
Although drug actions immediate, therapeutic effects may
take 2-3 weeks.
Antidepressants are generally effective in only about 60% of
patients.
– Other support:
Upregulation of MA receptors in brains of depressed
individuals who have not received pharmacological treatment
Drugs that deplete MAs produce depression (e.g., reserpine)
Other nonpharmacological tx increase MAs (e.g., ECT)
Study Objectives #13 and #18
DEPRESSION: Adrenal Function
Hypothalamic-Pituitary-Adrenal Axis
Cortisol Levels in Depression
Study Objective #14
DEPRESSION: Adrenal Function
Dexamethasone
Suppression
test
Neurotrophin
hypothesis
– Glucocorticoids
inhibit BDNF
– Antidepressants
may reverse
this effect
Study Objective #14
DEPRESSION: Sleep
Sleep abnormalities and depression
–
–
–
–
Reductions in SWS
shortened REM latency
altered temporal distribution of REM
more vigorous REMs (inc. REM/min.)
Study Objective #15
DEPRESSION: Sleep
Depression and REM sleep
– REM deprivation has antidepressant effects
Vogel et al. (1980) studies
3 weeks REM deprivation vs. nonREM deprivation
Reversal design
– Antidepressant drugs suppress REM sleep
DEPRESSION: Circadian Rhythms
Abnormal phase relationships in body
rhythms (e.g., s-w cycle and temp. cycle)
Treatment: shifting bed time improves
depression in some patients.
DEPRESSION: Circadian Rhythms
Seasonal Affective Disorder (SAD)
– Characterized by seasonal mood changes
(winter depression)
– Increased sleeping and eating (distinct from
other Major Depressive Disorders)
– Positive correlation between incidence of SAD
and latitude (some exceptions, e.g., Iceland)
– Primary treatment: phototherapy
– Involvement of melatonin???
DEPRESSION
Functional Brain Imaging
PET studies reveal neurological
abnormalities associated with depression
– increased blood flow in amygdala and frontal
cortex
– decreased blood flow in parietal and posterior
cortex
– normal cerebral blood flow in amygdala in
patients treated with antidepressants
Study Objective #12
ANXIETY DISORDERS
Generalized Anxiety Disorder
Panic Disorder
Phobias
Obsessive-Compulsive Disorder
Post-Traumatic Stress Disorder
Study Objective #19
ANXIETY DISORDERS
Pharmacological Treatments provide clues to
the underlying neuropathology
– Benzodiazepines (e.g. Valium, Xanax)
facilitate GABA-mediated postsynaptic inhibition
BDZ receptors heavily concentrated in cerebral cortex,
hippocampus, and amygdala
– BDZ antagonists facilitate panic attacks
– Evidence for endogenous anxiogenic peptides
associated with BDZ receptors
– Serotonin agonists may also be effective anxiolytics
SSRIs, Buspirone
Study Objective #20
PANIC DISORDER
Temporal Lobe Abnormalities in Panic
Disorder
– MRI studies by Ontiveros et al. (1989)
lesions in white matter and dilation of lateral
ventricles
– PET studies by Reiman et al. (1986)
Patients vulnerable to lactate-induced panic
showed abnormal increase in blood flow in
right parahippocampal gyrus.
Study Objective #21
PANIC DISORDER
Imaging studies indicate involvement of cingulate,
prefrontal, and anterior temporal cortex in panic
attacks.
– PET study by Fischer et al. (1998)
The cingulate, prefrontal, and anterior temporal cortex were
activated during a panic attack.
– rCBF study by Johanson et al., 1998
Participants were shown spider videos; responders showed
decreased frontal ctx activity, nonresponders showed
increased activity.
– fMRI study by Bystritsky et al. (2001)
PD patients imagined anxiety provoking situations; increased
activity occurred in inferior frontal ctx, cingulate ctx, and
hippocampus.
Obsessive Compulsive Disorder
Prevalence of OCD
– Estimated 4 million in US
– Peak age 25-44
Heritability
– Twin studies suggest genetic involvement
– Family studies link Tourette’s syndrome with OCD
Neurological abnormalities
– Higher metabolic rates in left orbital gyrus and
caudate nuclei.
Often co-morbid with depression
– Importance of serotonin: SSRIs markedly reduce
symptoms.
Study Objective #22
Neurobiology of OCD
Imaging studies suggest involvement of
– Oribitofrontal cortex
– Cingulate cortex
– Caudate nucleus
Breiter et al.(1996) study
– Handling of “contaminated” items produced
increased activity in orbitofrontal, cingulate,
basal ganglia, and amygdala.
Study Objective #22
Neurobiology of OCD
PET studies on OCD treatment changes
– Symptom remission is associated with
reduced activity in caudate and orbitofrontal
cortex.
– Cognitive-behavior therapy and
pharmacological therapy produce similar
changes in brain. Study Objective #22
Cingulotomy: a last resort
– The surgical destruction of the cingulum
bundle, which connects the prefrontal cortex
with the limbic system, helps reduce intense
anxiety and the symptoms of obsessivecompulsive disorder.
PTSD
Characteristic symptoms
– Recurrent dreams or memories of traumatic
event
– Avoidance behaviors, which may lead to
diminished interest in social activities
suppression of emotion and detachment from others
– Irritability, anger, difficulty concentrating,
heightened sensitivity to sudden noises or
movements
Prevalence
– Four times more likely in women than men
– Can occur at any age, although children show
particular symptoms not typically seen in adults
PTSD
Heritability
– Twin studies suggest genetic factors influence
likelihood of developing PTSD symptoms following
trauma
Risk Factors
–
–
–
–
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Earlier age at time of traumatic event
Exposure to more than one traumatic event
Father with depressive disorder
Low education level
Preexisting conduct disorder, panic disorder,
generalized anxiety disorder, or depressive disorder
PTSD
The psychobiological model of PTSD
emphasizes
– fear conditioning
a failure or fragility of extinction mechanisms
– behavioral sensitization
NMDA receptor mediated mechanisms important
in fear conditioning and extinction.
dopaminergic mechanisms in sensitization
Study Objective #23
PTSD: Neural Model
Study Objective #23
STRESS EFFECTS ON BRAIN
Animal Models
STRESS EFFECTS ON BRAIN
Effects of social stress on pyramidal cells
in the monkey hippocampus
PTSD Neuropathology
Perhaps stress-induced elevated cortisol levels
promote cell death and/or impede neurogenesis
in the hippocampus.
Patients with combat related PTSD exhibit signs
of amnesia, particularly short term memory
deficits. This may be linked to neuropathological
changes in the medial temporal lobe .
– e.g., MRI studies of combat veterans with PTSD show 8%
reduction in hippocampal volume.
– However, studies of twin pairs suggest that smaller hippocampus
may actually predate development of PTSD (Gilbertson et al.,
2002)
Study Objective #23
PTSD Neuropathology
Study Objective #23
Stress Hormones & PTSD
Regarding the hypothesis of stressinduced hippocampal damage in PTSD:
– Evidence shows that PTSD sufferers actually
have lower cortisol levels.
ER study of rape victims (Resnick et al.,1995)
Women with previous history of assault had highest
likelihood of developing PTSD and lowest cortisol
levels.
– High levels of CRH (not cortisol) may play a
role in the development of PTSD
Evidence that CRH levels are elevated and cortisol
levels are reduced in PTSD patients (Baker et al.,
1999)