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)