Handout for Biology of Mental Disorders (BCS 246)
Session 16 (11/7)

Clinical investigation

• Careful history taking for diagnosis is critical and most often neglected aspect of work up
• 3rd party input crucial (family, friends, support group who knows patient etc.)
• Personality style and development dissociated from onset of pathologic process
• Frequent failure to do this
• Must get background, then focus on point of departure from typical functioning to onset of new process resulting in psychiatric attention
• Differential diagnosis and search for etiology (many causes of psychiatric symptoms that need identification and elimination of offending factor)
• Do not see distinction of functional vs. structural being as clear as Trimble makes it
• There are structured clinical interviews that assure diagnosis is made with appropriate ruling out of other psychiatric syndromes, as well as symptom rating scales to assess change
• Structured Clinical Interview for DSM IV (SCID interview)
• Hamilton and Beck depression ratings, Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS) etc.
• Typical laboratory work up (not to be memorized!!!, but psychiatrists better know this)
• Basic serum tests, including: blood counts, renal functions, liver functions, test for acute inflammatory process (ESR), syphilis screen, vitamin B12 and folate levels, thyroid functions
• Sometimes: glucose tolerance test, serum copper if Wilson's disease suspected, antinuclear antibody if autoimmune disorder suspected, EEG, and MRI of head if suspect seizure disorder, first episode of psychosis, focal neurologic findings, change from treatment responsive to refractory
• Note: some brain disorders look very much like psychiatric syndromes and need to be ruled out (brain tumors [benign and malignant], encephalitis, temporal lobe epilepsy, generally limbic region pathology)
  
  

• Epidemiologic studies for examining incidence of disorders, relation to demographics, stability over time, whether accessing care professionals etc.
• Longitudinal studies of patients with disorder to examine comorbidity issues, changes over time within patients, response to treatment over time, predictors of prognosis etc.
• Genetic factors
• Family studies, twin studies, identical or monozygotic (MZ) vs. dizygotic (DZ) twin studies (concordance rates, best are adoption studies [raised together vs. apart])
• Genetic linkage studies
• Neuroendocrine function
• Prolactin levels, cortisol level after giving agent that should decrease it (dexamethasone suppression test), TRH stimulation test (to see responsiveness of hypothalamus), prolactin levels (prolactin release under dopaminergic control)
• Challenge studies
• Ex. Growth hormone response to apomorphine (dopamine agonist)
• Behavioral response to serotonin agonist/antagonist, serotonin depleting diet etc.
• Response to yohimbine (NE agonist)
• EEG and ERP studies (cortical brain electrical activity, averaged EEG due to stimuli)
• Abnormalities, relation to clinical picture, prediction of response, challenge studies
• Neuroimaging for structural and functional changes
• CT scan (computed x-ray tomography)
• MRI (magnetic resonance imaging)
• MRS (magnetic resonance spectroscopy)
• fMRI (functional MRI)
• PET (Positron Emission Tomography)
• SPECT scanning (Single Photon Emission Computed Tomography)
  
  

• Importance of differentiation between personality and psychiatric syndrome (Trimble emphasizes " neurosis" in this differentiation but many disorders involved)
• Generally, psychiatric disorders seen as a deviation or "process" different than extremes of personality
• Note that some feel states of "demoralization" occur in those without traits of personality disorders and those with these traits, both groups having a syndrome of moderate depression
• Given the confusion in this area, would expect much research: Well there isn't
• Would expect clinical "lore" to be studied: cyclothymic personality related to depression or manic depressive disorder, anxious personality styles related to panic, phobia, generalized anxiety disorder, hysterical personality disorder or traits related to somatization disorder

• Some evidence for obsessive-compulsive personality traits being very high in patients with obsessive compulsive disorder (is this a surprise?)
• Genetics of Neuroses
• Evidence of high degree of heritability for "anxiety neurosis" [I think he's referring to generalized anxiety disorder, panic disorder, obsessive compulsive disorder]
• MZ twins have greater concordance than DZ twins for obsessive compulsive disorder (highest rates)
• Also for phobic disorder
• Evidence for autosomal dominant transmission of Tourette's syndrome, with incomplete penetrance and obsessional traits as part of the inheritance
• Family members of OCD patients with higher incidence of obsessional symptoms
• Evidence of heritability of antisocial personality disorder
• Twin and adoption studies (particularly with MZ/DZ twins)
• US study also showing additive effects of genetic loading and home environment (one of few studies that show significant "shared environment" effect
• Heritability of personality traits supported by MZ vs. DZ twin studies and adoption studies (Minnesota data particularly)
• Note: Twins reared apart are more alike than twins reared together!!
• Also evidence that similarity increases with age (divergence in late adolescence/early adulthood with later "return" to greater similarity)
• Evidence for "shared environment" very limited, with heritability of almost all well assessed traits approximately 50% (introversion, extroversion, sensation seeking, negative/positive affect, even political conservatism!!!)
• Note the lack of this content in lay media vs. the generally accepted concept of early environmental trauma affecting personality (which has very limited evidence in good studies designed to detect this)
• For experimental psychologists one of the real mysteries is whether the non-heritable aspect of personality is "noise" or "unshared environment" [I put my money on an even split, with noise a statistical necessity and unshared environment being what is left in most of these studies: ?peer group, role models at school etc., I put my money on peer group but this is also not random]
• Specially bred animals (for "anxiety-like behavior") have noradrenergic and GABA (benzodiazepine sensitive) abnormalities
  • Somatic Variables
• Autonomic nervous system indices abnormal in anxiety disorders (Cluster C)
• Sweat gland activity
• Skin conductance
• Decreased habituation of skin conductance and acoustic startle
• Blood pressure
• Heart rate changes (sinus arrhythmia alterations)
• Mitral valve prolapse (heart valve problem)
  • Metabolic and Biochemical
• Anxiety much more easily stimulated in patients with anxiety disorders (central effects)
• Epinephrine (adrenaline) infusions
• Beta adrenergic stimulation
• Lactic acid infusion
• ? Lactic acid may cause effects due to its reducing calcium
• Monoamine oxidase (enzyme that breaks down catecholamines and serotonin, genetically determined)
• MMPI scales higher (and scales measuring "sensation seeking") in those with lowest MAO
• Children with low MAO much more active
• Adults with low MAO reported to be more impulsive, monotony avoidant, aggressive, suicidal, likely to have mental health contacts, likely to use illicit drugs, likely to be convicted, and have job instability
• MAO may be elevated in those with panic disorder (i.e. opposite of above and opposite personality traits?)
• Extremes of MAO may be related to "vulnerability" to certain personality traits
• Catecholamines
• Higher in anxiety disorder subjects, PTSD patients, and subjects with high self report of anxiety
• Pituitary hormone findings
• Blunted response to TRH (low output of thyroid stimulating hormone [TSH] given the hormone that should increase it, i.e. TRH)
• Reduced response of growth hormone (GH) to clonidine (alpha 2 receptor antagonist), which typically increases this hormone in "normals"
• Anxiety disorder patients and OCD patients have normal DST (dexamethasone suppression), so not all hypothalamic pathways are abnormal!
• Some borderline PD patients do have abnormal DST (i.e. abnormally high cortisol after given dexamethasone, which should suppress output of cortisol; i.e. abnormal function of negative feedback loop)
• Neurochemical findings
• Anxiety disorders
• Noradrenergic mechanisms implicated, with greater NE output after an agonist of alpha receptors (Yohimbine) in anxiety disorder patients
• Possible increased responsiveness of locus coeruleus (NE neurons)
• Benzodiazepines reduce anxiety and antagonists of benzodiazepine receptors increase anxiety (and there are large numbers of BZ receptors in limbic brain regions)
  • Aggression findings
• Low serotonin activity most implicated
• Possible link to MAO activity but this is not intuitive given the findings (low MAO should increase serotonin availability)
  • Obsessive Compulsive Disorder
• Serotonin indirectly implicated due to efficacy of 5HT enhancing medication (Enafranil, SSRIs) and "blunted" prolactin increase with 5HT agonist (fenfluramine)
• Pretreatment serotonin levels and change in serotonin linked to successful treatment
• Cholinergic system hypersensitivity noted (exaggerated increase in GH with ACh enhancement)
• Normal NE responsivity, DST
  • Neurophysiologic and Neurologic Data
• EEG abnormalities in impulsive subjects and those with criminality (particularly aggressive)
• "Hypofrontality" on PET scanning noted in violent criminals
• Inter-ictal syndrome of TLE (humorlessness, circumstantiality, hypergraphia, hyper-religious, mystical interests, obsessional, feeling of special role often Messianic)
• Functional "hyperconnection" syndrome (between limbic & neocortical areas)
• Functional imaging in anxiety shows many cortical areas with increased metabolism
• OCD patients benefit from cingulate gyrus disruption (surgery)
• Functional imaging in OCD most consistent
• Increased metabolism in orbito-frontal, caudate nucleus, and thalamus
• Increases reduced with successful treatment (meds or behavior therapy)