neuropsychiatric disorders schizophrenia affective disorders anxiety disorders
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Neuropsychiatric DisordersNeuropsychiatric Disorders
SchizophreniaSchizophrenia
Affective DisordersAffective Disorders
Anxiety DisordersAnxiety Disorders
SCHIZOPHRENIASCHIZOPHRENIASymptomsSymptoms– Positive: i.e., noted by presence Positive: i.e., noted by presence
(dissociative, illogical thought, delusions, (dissociative, illogical thought, delusions, hallucinations)hallucinations)
– Negative: i.e., noted by absence Negative: i.e., noted by absence
(social withdrawal, blunted affect, poverty of (social withdrawal, blunted affect, poverty of thought/speech)thought/speech)
PrevalencePrevalence– 1% of population1% of population– universal disorder, i.e. all races and culturesuniversal disorder, i.e. all races and cultures
Study Objective #1
SCHIZOPHRENIASCHIZOPHRENIA
Heritability and Genetic FactorsHeritability and Genetic Factors– Family StudiesFamily Studies
increased risk with family historyincreased risk with family history– Twin StudiesTwin Studies
concordance rates of monozygotic vs. concordance rates of monozygotic vs. dizygotic twinsdizygotic twins
– Adoption StudiesAdoption Studies
biological vs. adoptive parentsbiological vs. adoptive parents
Study Objective #2
SCHIZOPHRENIASCHIZOPHRENIA
Study Objective #2
SCHIZOPHRENIASCHIZOPHRENIA
Causes?Causes?– Multiple causesMultiple causes– Several genes implicated in vulnerability Several genes implicated in vulnerability
to schizophreniato schizophrenia– Multiple experiential factors possible Multiple experiential factors possible
contributorscontributors e.g., infections, autoimmune reactions, e.g., infections, autoimmune reactions, toxins, traumatic injury, stresstoxins, traumatic injury, stress
ANTIPSYCHOTIC DRUGSANTIPSYCHOTIC DRUGS
Discovery of Chlorpromazine – 1950sDiscovery of Chlorpromazine – 1950s– Laborit examined phenothiazines to prevent Laborit examined phenothiazines to prevent
post-surgical shockpost-surgical shock
ReserpineReserpine– derived from snake root plant in Indiaderived from snake root plant in India– antischizophrenic effects, but causes severe antischizophrenic effects, but causes severe
hypotensionhypotension
HaloperidolHaloperidol– ButyrophenoneButyrophenone– D2 dopamine antagonistD2 dopamine antagonist
Atypical Neuroleptics Atypical Neuroleptics – e.g., clozapine, risperidone e.g., clozapine, risperidone
Study Objective #6
ANTIPSYCHOTIC DRUGSANTIPSYCHOTIC DRUGS
Side Effects of Classical NeurolepticsSide Effects of Classical NeurolepticsParkinsonian featuresParkinsonian features
Tardive DyskinesiaTardive Dyskinesia
Atypical AntipsychoticsAtypical AntipsychoticsDo not produce motor side effectsDo not produce motor side effects
Some evidence that clozapine may improve or Some evidence that clozapine may improve or reverse TD symptomsreverse TD symptoms
Clozapine and agranulocytosisClozapine and agranulocytosis
Study Objective #10
ANTIPSYCHOTIC DRUGSANTIPSYCHOTIC DRUGSReceptor Binding Affinities of a Variety of Receptor Binding Affinities of a Variety of Antipsychotic DrugsAntipsychotic Drugs
DOPAMINE HYPOTHESISDOPAMINE HYPOTHESIS
Early clues to the dopamine link to Early clues to the dopamine link to schizophrenia:schizophrenia:– Parkinsonian side effects of the first Parkinsonian side effects of the first
antipsychotic drugs (1950s) antipsychotic drugs (1950s) – Clinical observations of amphetamine-Clinical observations of amphetamine-
induced psychosis (1960s)induced psychosis (1960s)– Discoveries of antipsychotic drug receptor Discoveries of antipsychotic drug receptor
pharmacology (1970s)pharmacology (1970s)
Study Objectives #5 and #7
DOPAMINE HYPOTHESISDOPAMINE HYPOTHESISCriticisms of the DA hypothesis:Criticisms of the DA hypothesis:– Delayed onset of therapeutic effects relative to the Delayed onset of therapeutic effects relative to the
pharmacological effects:pharmacological effects:
slow developing compensatory change, such as DA cell slow developing compensatory change, such as DA cell
depolarization block may account for therapeutic effectsdepolarization block may account for therapeutic effects
– Normal levels of DA metabolites are present in CSF of Normal levels of DA metabolites are present in CSF of
many schizophrenics.many schizophrenics.
– Results of postmortem and PET studies of D2 receptor Results of postmortem and PET studies of D2 receptor
density are inconsistent. (Pinel fails to address this.)density are inconsistent. (Pinel fails to address this.)
– Atypical Antipsychotic Drugs (e.g., clozapine, risperidol) Atypical Antipsychotic Drugs (e.g., clozapine, risperidol)
have relatively low D2 binding affinities, and greater affinity have relatively low D2 binding affinities, and greater affinity
for D1, D3, or D4 receptors as well as 5-HT receptors. for D1, D3, or D4 receptors as well as 5-HT receptors.
Study Objectives #8 and #9
GLUTAMATE INVOLVEMENTGLUTAMATE INVOLVEMENT
– PCP models of psychosisPCP models of psychosis
Chronic PCP produces negative symptoms and reduces Chronic PCP produces negative symptoms and reduces
metabolic activity in prefrontal cortex.metabolic activity in prefrontal cortex.
PCP blocks NMDA glutamate receptors.PCP blocks NMDA glutamate receptors.
– NMDA receptor hypofunction hypothesisNMDA receptor hypofunction hypothesis
NMDA receptor hypofunction causes excessive NMDA receptor hypofunction causes excessive
glutamate release which triggers neuronal injury glutamate release which triggers neuronal injury
throughout corticolimbic regions.throughout corticolimbic regions.
This might account for negative symptoms and the This might account for negative symptoms and the
cognitive deterioration associated with schizophrenia.cognitive deterioration associated with schizophrenia.
PCP RECEPTORPCP RECEPTOR
Effects of PCP Effects of PCP Model of PCP receptor Model of PCP receptor
HYPOFRONTALITY HYPOTHESISHYPOFRONTALITY HYPOTHESIS
Hypofrontality: reduced frontal lobe activityHypofrontality: reduced frontal lobe activity
– Functional imaging techniques (fMRI, PET, SPECT) Functional imaging techniques (fMRI, PET, SPECT)
reveal decreased metabolic activity in frontal cortex of reveal decreased metabolic activity in frontal cortex of
schizophrenics.schizophrenics.
– Difficult cognitive tasks that increase frontal lobe Difficult cognitive tasks that increase frontal lobe
activity in normal controls fail to do so in activity in normal controls fail to do so in
schizophrenics.schizophrenics.e.g., Wisconsin Card Sorting Taske.g., Wisconsin Card Sorting Task
– PCP produces hypofrontality in nonhuman primates, PCP produces hypofrontality in nonhuman primates, and this effect is reversed by antipsychotic drugs.and this effect is reversed by antipsychotic drugs.
Study Objective #4
NEUROPATHOLOGY OF NEUROPATHOLOGY OF SCHIZOPHRENIASCHIZOPHRENIA
Enlarged cerebral ventricles and reduced Enlarged cerebral ventricles and reduced cortical volume (cortical volume (signs of tissue atrophy)signs of tissue atrophy)– Tissue loss most evident in prefrontal, cingulate, Tissue loss most evident in prefrontal, cingulate,
and medial temporal cortexand medial temporal cortex
Study Objective #3
SCHIZOPHRENIASCHIZOPHRENIA– Limbic system abnormalitiesLimbic system abnormalities
Hippocampus: Hippocampus: disoriented pyramidal cellsdisoriented pyramidal cells
Parahippocampal and entorhinal cortexParahippocampal and entorhinal cortex
Cingulate CortexCingulate Cortex
AFFECTIVE DISORDERSAFFECTIVE DISORDERS
CategoriesCategories– Bipolar Affective DisorderBipolar Affective Disorder– Unipolar Affective DisorderUnipolar Affective Disorder
Reactive Depression (clearly triggered by Reactive Depression (clearly triggered by environmental event)environmental event)
Endogenous Depression (no obvious Endogenous Depression (no obvious environmental cause)environmental cause)
DEPRESSIONDEPRESSION
SymptomsSymptoms– mood changes, lost interest, energy and appetite, mood changes, lost interest, energy and appetite,
concentration difficulties, restless agitationconcentration difficulties, restless agitation
PrevalencePrevalence– 5% males, 8% females5% males, 8% females
HeritabilityHeritability– Twin studies 70% concordance in mz vs. 20% in dz Twin studies 70% concordance in mz vs. 20% in dz
twinstwins– Adoption studies: higher rates in biological vs foster Adoption studies: higher rates in biological vs foster
parentsparents
Study Objective #11
DEPRESSION AND SUICIDEDEPRESSION AND SUICIDE
~ 80% of suicide victims depressed~ 80% of suicide victims depressedResearch has shownResearch has shown– lower 5-HT levels in suicide attempters.lower 5-HT levels in suicide attempters.– higher cortisol levels in suicide attempters.higher cortisol levels in suicide attempters.
Some evidence for genetic anomalies in Some evidence for genetic anomalies in suicidal individualssuicidal individuals– e.g., A variant version of gene for 5-HTe.g., A variant version of gene for 5-HT2A2A
receptor is more common in suicide victims receptor is more common in suicide victims vs. controls.vs. controls.
DEPRESSION: TreatmentsDEPRESSION: Treatments
TreatmentsTreatments– Pharmacological treatmentsPharmacological treatments– REM deprivationREM deprivation– Electroconvulsive Therapy (ECT)Electroconvulsive Therapy (ECT)
limited to severe caseslimited to severe cases
Study Objective #16
ANTIDEPRESSANT DRUGSANTIDEPRESSANT DRUGSserendipitous discoveriesserendipitous discoveries
MAOIsMAOIs– Iproniazid in tuberculosis treatment, 1950sIproniazid in tuberculosis treatment, 1950s– potential side effects: hypertensive crisis with potential side effects: hypertensive crisis with
tyramine rich foodstyramine rich foods
TricyclicsTricyclics– Imipramine first tested as an antipsychotic Imipramine first tested as an antipsychotic
LithiumLithium– John Cade’s discoveries in experiments with John Cade’s discoveries in experiments with
guinea pigsguinea pigs
SSRIs and SNRIsSSRIs and SNRIs
Study Objective #17
ANTIDEPRESSANT DRUGSANTIDEPRESSANT DRUGSmechanisms of actionmechanisms of action
Study Objective #17
DEPRESSION: Neural MechanismsDEPRESSION: Neural Mechanisms
Monoamine TheoryMonoamine Theory– Decreased 5-HT/NE activityDecreased 5-HT/NE activity– Main support: efficacy of pharmacological treatmentsMain support: efficacy of pharmacological treatments
i.e., monoaminergic actions of antidepressants i.e., monoaminergic actions of antidepressants – Criticisms:Criticisms:
Although drug actions immediate, therapeutic effects may Although drug actions immediate, therapeutic effects may take 2-3 weeks.take 2-3 weeks.Antidepressants are generally effective in only about 60% of Antidepressants are generally effective in only about 60% of patients.patients.
– Other support:Other support:Upregulation of MA receptors in brains of depressed Upregulation of MA receptors in brains of depressed individuals who have not received pharmacological treatmentindividuals who have not received pharmacological treatmentDrugs that deplete MAs produce depression (e.g., reserpine)Drugs that deplete MAs produce depression (e.g., reserpine)Other nonpharmacological tx increase MAs (e.g., ECT)Other nonpharmacological tx increase MAs (e.g., ECT)
Study Objectives #13 and #18
DEPRESSION: Adrenal FunctionDEPRESSION: Adrenal FunctionHypothalamic-Pituitary-Adrenal AxisHypothalamic-Pituitary-Adrenal Axis
Cortisol Levels in DepressionCortisol Levels in Depression
Study Objective #14
DEPRESSION: Adrenal FunctionDEPRESSION: Adrenal Function
Dexamethasone Dexamethasone Suppression Suppression testtest
Neurotrophin Neurotrophin hypothesishypothesis– Glucocorticoids Glucocorticoids
inhibit BDNFinhibit BDNF– Antidepressants Antidepressants
may reverse may reverse this effectthis effect
Study Objective #14
DEPRESSION: SleepDEPRESSION: SleepSleep abnormalities and depressionSleep abnormalities and depression– Reductions in SWSReductions in SWS– shortened REM latencyshortened REM latency– altered temporal distribution of REMaltered temporal distribution of REM– more vigorous REMs (inc. REM/min.)more vigorous REMs (inc. REM/min.)
Study Objective #15
DEPRESSION: SleepDEPRESSION: Sleep
Depression and REM sleepDepression and REM sleep– REM deprivation has antidepressant effectsREM deprivation has antidepressant effects
Vogel et al. (1980) studiesVogel et al. (1980) studies
3 weeks REM deprivation vs. nonREM deprivation3 weeks REM deprivation vs. nonREM deprivation
Reversal designReversal design
– Antidepressant drugs suppress REM sleepAntidepressant drugs suppress REM sleep
DEPRESSION: Circadian RhythmsDEPRESSION: Circadian Rhythms
Abnormal phase relationships in body Abnormal phase relationships in body rhythms (e.g., s-w cycle and temp. cycle)rhythms (e.g., s-w cycle and temp. cycle)
Treatment: shifting bed time improves Treatment: shifting bed time improves depression in some patients.depression in some patients.
DEPRESSION: Circadian RhythmsDEPRESSION: Circadian Rhythms
Seasonal Affective Disorder (SAD)Seasonal Affective Disorder (SAD)– Characterized by seasonal mood changes Characterized by seasonal mood changes
(winter depression)(winter depression)– Increased sleeping and eating (distinct from Increased sleeping and eating (distinct from
other Major Depressive Disorders)other Major Depressive Disorders)– Positive correlation between incidence of SAD Positive correlation between incidence of SAD
and latitude (some exceptions, e.g., Iceland)and latitude (some exceptions, e.g., Iceland)– Primary treatment: phototherapyPrimary treatment: phototherapy– Involvement of melatonin???Involvement of melatonin???
DEPRESSIONDEPRESSIONFunctional Brain ImagingFunctional Brain Imaging
PET studies reveal neurological PET studies reveal neurological abnormalities associated with depressionabnormalities associated with depression– increased blood flow in amygdala and frontal increased blood flow in amygdala and frontal
cortexcortex– decreased blood flow in parietal and posterior decreased blood flow in parietal and posterior
cortexcortex– normal cerebral blood flow in amygdala in normal cerebral blood flow in amygdala in
patients treated with antidepressantspatients treated with antidepressants
Study Objective #12
ANXIETY DISORDERSANXIETY DISORDERS
Generalized Anxiety DisorderGeneralized Anxiety DisorderPanic DisorderPanic DisorderPhobiasPhobiasObsessive-Compulsive DisorderObsessive-Compulsive DisorderPost-Traumatic Stress DisorderPost-Traumatic Stress Disorder
Study Objective #19
ANXIETY DISORDERSANXIETY DISORDERSPharmacological Treatments provide clues to Pharmacological Treatments provide clues to the underlying neuropathologythe underlying neuropathology– Benzodiazepines (e.g. Valium, Xanax)Benzodiazepines (e.g. Valium, Xanax)
facilitate GABA-mediated postsynaptic inhibitionfacilitate GABA-mediated postsynaptic inhibition
BDZ receptors heavily concentrated in cerebral cortex, BDZ receptors heavily concentrated in cerebral cortex, hippocampus, and amygdalahippocampus, and amygdala
– BDZ antagonists facilitate panic attacks BDZ antagonists facilitate panic attacks – Evidence for endogenous anxiogenic peptidesEvidence for endogenous anxiogenic peptides
associated with BDZ receptorsassociated with BDZ receptors
– Serotonin agonists may also be effective anxiolyticsSerotonin agonists may also be effective anxiolyticsSSRIs, BuspironeSSRIs, Buspirone
Study Objective #20
PANIC DISORDERPANIC DISORDER
Temporal Lobe Abnormalities in Panic Temporal Lobe Abnormalities in Panic DisorderDisorder– MRI studies by Ontiveros et al. (1989)MRI studies by Ontiveros et al. (1989)
lesions in white matter and dilation of lateral lesions in white matter and dilation of lateral ventriclesventricles
– PET studies by Reiman et al. (1986)PET studies by Reiman et al. (1986)Patients vulnerable to lactate-induced panic Patients vulnerable to lactate-induced panic showed abnormal increase in blood flow in showed abnormal increase in blood flow in right parahippocampal gyrus.right parahippocampal gyrus.
Study Objective #21
PANIC DISORDERPANIC DISORDERImaging studies indicate involvement of cingulate, Imaging studies indicate involvement of cingulate, prefrontal, and anterior temporal cortex in panic prefrontal, and anterior temporal cortex in panic attacks.attacks.– PET study by Fischer et al. (1998)PET study by Fischer et al. (1998)
The cingulate, prefrontal, and anterior temporal cortex were The cingulate, prefrontal, and anterior temporal cortex were activated during a panic attack.activated during a panic attack.
– rCBF study by Johanson et al., 1998rCBF study by Johanson et al., 1998Participants were shown spider videos; responders showed Participants were shown spider videos; responders showed decreased frontal ctx activity, nonresponders showed decreased frontal ctx activity, nonresponders showed increased activity.increased activity.
– fMRI study by Bystritsky et al. (2001)fMRI study by Bystritsky et al. (2001)PD patients imagined anxiety provoking situations; increased PD patients imagined anxiety provoking situations; increased activity occurred in inferior frontal ctx, cingulate ctx, and activity occurred in inferior frontal ctx, cingulate ctx, and hippocampus.hippocampus.
Obsessive Compulsive DisorderObsessive Compulsive Disorder
Prevalence of OCDPrevalence of OCD– Estimated 4 million in USEstimated 4 million in US– Peak age 25-44Peak age 25-44
HeritabilityHeritability– Twin studies suggest genetic involvementTwin studies suggest genetic involvement– Family studies link Tourette’s syndrome with OCDFamily studies link Tourette’s syndrome with OCD
Neurological abnormalitiesNeurological abnormalities– Higher metabolic rates in left orbital gyrus and Higher metabolic rates in left orbital gyrus and
caudate nuclei.caudate nuclei.
Often co-morbid with depressionOften co-morbid with depression– Importance of serotonin: SSRIs markedly reduce Importance of serotonin: SSRIs markedly reduce
symptoms.symptoms.
Study Objective #22
Neurobiology of OCDNeurobiology of OCDImaging studies suggest involvement ofImaging studies suggest involvement of– Oribitofrontal cortexOribitofrontal cortex– Cingulate cortexCingulate cortex– Caudate nucleusCaudate nucleus
Breiter et al.(1996) studyBreiter et al.(1996) study– Handling of “contaminated” items produced Handling of “contaminated” items produced
increased activity in orbitofrontal, cingulate, increased activity in orbitofrontal, cingulate, basal ganglia, and amygdala.basal ganglia, and amygdala.
Study Objective #22
Neurobiology of OCDNeurobiology of OCD
PET studies on OCD treatment changesPET studies on OCD treatment changes– Symptom remission is associated with Symptom remission is associated with
reduced activity in caudate and orbitofrontal reduced activity in caudate and orbitofrontal cortex.cortex.
– Cognitive-behavior therapy and Cognitive-behavior therapy and pharmacological therapy produce similar pharmacological therapy produce similar changes in brain. changes in brain.
Cingulotomy: a last resortCingulotomy: a last resort– The surgical destruction of the cingulum The surgical destruction of the cingulum
bundle, which connects the prefrontal cortex bundle, which connects the prefrontal cortex with the limbic system, helps reduce intense with the limbic system, helps reduce intense anxiety and the symptoms of obsessive-anxiety and the symptoms of obsessive-compulsive disorder.compulsive disorder.
Study Objective #22
PTSDPTSDCharacteristic symptomsCharacteristic symptoms– Recurrent dreams or memories of traumatic Recurrent dreams or memories of traumatic
eventevent– Avoidance behaviors, which may lead toAvoidance behaviors, which may lead to
diminished interest in social activitiesdiminished interest in social activitiessuppression of emotion and detachment from otherssuppression of emotion and detachment from others
– Irritability, anger, difficulty concentrating, Irritability, anger, difficulty concentrating, heightened sensitivity to sudden noises or heightened sensitivity to sudden noises or movementsmovements
PrevalencePrevalence– Four times more likely in women than menFour times more likely in women than men– Can occur at any age, although children show Can occur at any age, although children show
particular symptoms not typically seen in adultsparticular symptoms not typically seen in adults
PTSDPTSDHeritabilityHeritability– Twin studies suggest genetic factors influence Twin studies suggest genetic factors influence
likelihood of developing PTSD symptoms following likelihood of developing PTSD symptoms following traumatrauma
Risk FactorsRisk Factors– Earlier age at time of traumatic eventEarlier age at time of traumatic event– Exposure to more than one traumatic eventExposure to more than one traumatic event– Father with depressive disorderFather with depressive disorder– Low education levelLow education level– Preexisting conduct disorder, panic disorder, Preexisting conduct disorder, panic disorder,
generalized anxiety disorder, or depressive disordergeneralized anxiety disorder, or depressive disorder
PTSDPTSD
The psychobiological model of PTSD The psychobiological model of PTSD emphasizes emphasizes – fear conditioningfear conditioning
a failure or fragility of extinction mechanismsa failure or fragility of extinction mechanisms
– behavioral sensitizationbehavioral sensitizationNMDA receptor mediated mechanisms important NMDA receptor mediated mechanisms important in fear conditioning and extinction.in fear conditioning and extinction.
dopaminergic mechanisms in sensitizationdopaminergic mechanisms in sensitization
Study Objective #23
PTSD: Neural ModelPTSD: Neural Model
Study Objective #23
STRESS EFFECTS ON BRAIN STRESS EFFECTS ON BRAIN Animal ModelsAnimal Models
STRESS EFFECTS ON BRAINSTRESS EFFECTS ON BRAINEffects of social stress on pyramidal cells Effects of social stress on pyramidal cells in the monkey hippocampusin the monkey hippocampus
PTSD NeuropathologyPTSD Neuropathology
Perhaps stress-induced elevated cortisol levels Perhaps stress-induced elevated cortisol levels promote cell death and/or impede neurogenesis promote cell death and/or impede neurogenesis in the hippocampus.in the hippocampus.
Patients with combat related PTSD exhibit signs Patients with combat related PTSD exhibit signs of amnesia, particularly short term memory of amnesia, particularly short term memory deficits. This may be linked to neuropathological deficits. This may be linked to neuropathological changes in the medial temporal lobe .changes in the medial temporal lobe .– e.g., MRI studies of combat veterans with PTSD show 8% e.g., MRI studies of combat veterans with PTSD show 8%
reduction in hippocampal volume.reduction in hippocampal volume.– However, studies of twin pairs suggest that smaller However, studies of twin pairs suggest that smaller
hippocampus may actually predate development of PTSD hippocampus may actually predate development of PTSD (Gilbertson et al., 2002)(Gilbertson et al., 2002)
Study Objective #23
PTSD NeuropathologyPTSD Neuropathology
Study Objective #23
Stress Hormones & PTSD Stress Hormones & PTSD Regarding the hypothesis of stress-Regarding the hypothesis of stress-induced hippocampal damage in PTSD:induced hippocampal damage in PTSD:– Evidence shows that PTSD sufferers actually Evidence shows that PTSD sufferers actually
have have lowerlower cortisol levels. cortisol levels.ER study of rape victims (Resnick et al.,1995) ER study of rape victims (Resnick et al.,1995) Women with previous history of assault had highest Women with previous history of assault had highest likelihood of developing PTSD and lowest cortisol likelihood of developing PTSD and lowest cortisol levels.levels.
– High levels of CRH (not cortisol) may play a High levels of CRH (not cortisol) may play a role in the development of PTSDrole in the development of PTSD
Evidence that CRH levels are elevated and cortisol Evidence that CRH levels are elevated and cortisol levels are reduced in PTSD patients (Baker et al., levels are reduced in PTSD patients (Baker et al., 1999)1999)
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