Neuropsychiatric Disorders Schizophrenia Affective Disorders Anxiety Disorders

SCHIZOPHRENIA Symptoms Prevalence 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 Reserpine 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 amphetamine-induced 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 Prevalence Heritability 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 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. 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 obsessive-compulsive disorder. Study Objective #22

PTSD Characteristic symptoms Prevalence 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 Risk Factors Twin studies suggest genetic factors influence likelihood of developing PTSD symptoms following trauma Risk Factors 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 stress-induced 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)