Beruflich Dokumente
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To understand both the benefits and limitations of studying a behaviorally-described rather than physiologically-defined disorder
Eugene Bleuler
In 1911 coined the term schizophrenia, meaning splitting (or more accurately, fracturing) of the mind. Note this is NOT intended to imply split personalities but rather a split between thought and emotion
Sanders A. Don't confuse schizophrenia with multiple personality. Tex Med. 1993 Mar;89(3):8. PMID: 8451749
Diagnosis of Schizophrenia - I
A. Characteristic symptoms: > 2 of 5 of the following symptoms:
(1) delusions (2) hallucinations (3) disorganized speech (e.g., frequent derailment or incoherence) (4) grossly disorganized or catatonic behavior (5) negative symptoms, i.e., affective flattening, alogia, or avolition
Note: Only one Criterion A symptom is required if bizarre delusions or running commentary voices or voices conversing with each other.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). American Psychiatric Press; 1994 ISBN: 0890420629
Diagnosis of Schizophrenia - II
B. Social/occupational dysfunction. C. Duration: Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual symptoms. D. Schizoaffective and Mood Disorder exclusion. E. Substance / general medical condition exclusion. F. No Relationship to a Pervasive Developmental Disorder: If there is a history of Autistic Disorder or another Pervasive Developmental Disorder, the additional diagnosis of Schizophrenia is made only if prominent delusions or hallucinations are also present for at least a month (or less if successfully treated).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). American Psychiatric Press; 1994 ISBN: 0890420629
Schizophrenia symptoms
Watch Video From Abnormal Psychology, 3rd edition Barlow & Durand
Differential Diagnosis
Mania Depression with psychotic features Personality Disorders Drug induced psychosis Extreme OCD PTSD NOT dual personality Malingering or multiple personality disorders etc.
Subtypes
DSM-IV Subtypes - hierarchy in the order of consideration
Catatonic
Catatonic behavior dominates Less common nowadays Medical supportive care, benzodiazepines may help, consider ECT Disorganized speech, behavior, and affect (flat or inappropriate) Delusions and/or auditory hallucinations Not limited to persecutory themes Tends to have a later onset and better course
Undifferentiated - not above, but Criterion A still met Residual - Criterion A not currently met
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). American Psychiatric Press; 1994 ISBN: 0890420629
Neurodevelopmental vs Neurodegenerative
Neurodevelopmental Risk for illness can be influenced by prenatal events Presence of MPA (minor physical anomalies) in adults with schizophrenia Post-mortem studies reveal markers of aberrant neurodevelopment (abnormal migration) Neurodegenerative Disorder Classic definition and observation of natural course brain changes such as shrinkage occur after onset of illness Early treatment known to alter course of disease Relapse rates reflect influence of external factors
Neurodevelopment
Obstetrical complications and prenatal infections are two potential non-genetic early influences on neurodevelopment Genes influencing neuronal migration and other aspects of brain development are also candidates to explain abnormalities in neurodevelopment in schizophrenia Is schizophrenia neurodevelopmental or neurodegenerative or some combination? Some now view schizophrenia as a progressive neurodevelopmental disorder (DeLisi et al. 1997; Gur et al. 1998; Rapoport et al. 1999)
Kaplan HI, Sadock BJ (eds). Synopsis of Psychiatry, 8th Edition. Lippincott, Williams & Wilkins. 1998, ISBN: 0683303309 Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. McGraw-Hill Professional Publishing. 2000, ISBN: 0838577016.
Epidemiology - I
Lifetime prevalence ~1%; male = female
Quick review of incidence (new cases) versus prevalence (all cases)
Prevalence Figures: National Comorbidity Survey (NCS; Kessler et al., 1994); ECA, Environmental Catchment Study
Epidemiology - II
Increased mortality rate from accidents and natural causes:
life span is shortened by about a decade some under-diagnosis of medical illness is present
Illness seems concentrated in urban settings, i.e., it is somewhat correlated with population density in larger cities. Illness seems concentrated in lower socioeconomic classes.
downward drift vs. social causation
Kaplan HI, Sadock BJ (eds). Synopsis of Psychiatry, 8th Edition. Lippincott, Williams & Wilkins. 1998, ISBN: 0683303309
Epidemiology - III
High Co-morbidity with Substance Use ~75% nicotine; ~40% alcohol; ~20% marijuana; ~10% cocaine Substance use comorbidity worsens prognosis. ~1/3 or more of homeless population Disabling (over 50% unemployed) Costly for individual and society High number years of productive life lost 2.5% of all health care expenditures 50% of all inpatient psychiatry beds 30% of all hospitalizations $50 billion annual cost to US (direct + indirect)
Kaplan HI, Sadock BJ (eds). Synopsis of Psychiatry, 8th Edition. Lippincott, Williams & Wilkins. 1998, ISBN: 0683303309 Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. McGraw-Hill Professional Publishing. 2000, ISBN: 0838577016.
Clinical course
Prodrome Acute index episode (~first hospitalization) Relapsing, remitting course
Generally, there are some prodromal signs & symptoms prior to the first acute episode These most commonly appear as attenuated Criterion A symptoms of schizophrenia and social dysfunction They can also be thought of as the symptoms of Cluster A (odd & eccentric) Personality Disorders, e.g., Paranoid, Schizoid, and/or Schizotypal Personality Disorders
Prodrome
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). American Psychiatric Press; 1994 ISBN: 0890420629
Course
Classically, course consists of exacerbations and remissions, though often not to baseline premorbid level of functioning Illness progression often plateaus at 5 10 years after initial diagnosis Antipsychotic medications improve acute and long-term outcome About 1/4 have a good outcome, 1/4 continue to have moderate symptoms, and 1/2 remain significantly impaired with current treatment, these numbers are changing with improved pharmacologic treatments and can be altered with therapy
Kaplan HI, Sadock BJ (eds). Synopsis of Psychiatry, 8th Edition. Lippincott, Williams & Wilkins. 1998, ISBN: 0683303309
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). American Psychiatric Press; 1994 ISBN: 0890420629 Kaplan HI, Sadock BJ (eds). Synopsis of Psychiatry, 8th Edition. Lippincott, Williams & Wilkins. 1998, ISBN: 0683303309
Violence
Media distortions and sensationalism contribute to the idea that most schizophrenics are violent, but this is largely untrue. However, after factoring out comorbid disorders well known for increasing violence (e.g., alcoholism, antisocial personality disorder), an elevated risk remains compared to the general population Best predictors are history of previous violence, along with dangerous behavior while hospitalized and hallucinations or delusions involving violence
Kaplan HI, Sadock BJ (eds). Synopsis of Psychiatry, 8th Edition. Lippincott, Williams & Wilkins. 1998, ISBN: 0683303309 Brennan PA, Mednick SA, Hodgins S. Major mental disorders and criminal violence in a Danish birth cohort. Arch Gen Psychiatry. 2000 May;57(5):494-500. PMID: 10807490
Genetic epidemiology
Family studies
Show increased risk for illness to relatives of probands (schizophrenics) vs. relatives of controls This risk falls off rapidly as the relationship becomes more distant Schizophrenia spectrum, such as schizotypal personality disorder
Twin studies
Show increased diagnostic concordance rate for monozygotic (identical) vs. dizygotic (fraternal) twins; usually a 3-4:1 ratio Heritability estimates are around 80% Monozygotic concordances of 40-50% are strong evidence for the importance of environmental components
Adoption studies
Show increased risk for biological vs. adoptive relatives of patients with schizophrenia
Segregation analyses
Attempt to fit observed families with modes of inheritance, but have not succeeded with schizophrenia
Basal ganglia
Decreased number of D2 dopamine receptors
Kaplan HI, Sadock BJ (eds). Synopsis of Psychiatry, 8th Edition. Lippincott, Williams & Wilkins. 1998, ISBN: 0683303309 Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. McGraw-Hill Professional Publishing. 2000, ISBN: 0838577016.
Post-Mortem Neuroanatomy
Disturbed connection between thalamus and PFC
Subset of patients drink water to excess & develop hyponatremia Some neurophysiological traits are strongly associated with illness and may be biological markers:
Abnormal smooth pursuit eye movements Deficits in sensorimotor gating of auditory stimuli more later
Other problems with information processing at higher levels (more like neuropsychology):
Halstead-Reitan and Luria-Nebraska batteries Consistent with bilateral frontal & temporal dysfunction Impairments in sustained and selective attention (e.g., CPT), retention time, & problem-solving (executive functioning, especially sequencing), visual perception (fusiform gyrus?) Some decreased intelligence as measured by IQ tests as a group
Kaplan HI, Sadock BJ (eds). Synopsis of Psychiatry, 8th Edition. Lippincott, Williams & Wilkins. 1998, ISBN: 0683303309
Neurotransmitters
Agonists and Antagonists
Drugs that bind with receptors on the post-synaptic (and sometimes pre-synaptic) membrane fall into two groups: Agonists: Bind to receptors and simulate or enhance a neurotransmitter's actions (i.e., opening ion channels and causing EPSPs or IPSPs). Antagonists : Have the opposite effect of agonists by blocking the receptors and inactivating it (usually by taking up the space but without specifically causing the opening of the channel or the operation of the secondary messenger). The neurotransmitter's effect is nullified or diminished.
Glutamate
Disorganized thought symptoms of schizophrenia attributed to hypofunctional glutamate system Glutamate antagonists such as PCP and ketamine mimic disorganized thought, may also cause psychosis and negative symptoms?
Neurotransmitters - I
Dopamine hypothesis - strengths:
Substances leading to increased dopaminergic states cause psychosis. Another way of stating this is that L-DOPA, amphetamine, and cocaine are psychotomimetic. Antidopaminergic agents are antipsychotic, and there is a good correlation for classical antipsychotics between their potency and their D2 dopamine receptor binding Pretreatment correlations of plasma homovanillic acid (major dopamine metabolite) with severity of psychotic symptoms and treatment response Antipsychotics work for psychosis due to many other etiologies in addition to schizophrenia Some atypical antipsychotics such as clozapine are not as well correlated with respect to D2 dopamine receptor binding and clinical potency Does not account for negative symptoms of schizophrenia
Kaplan HI, Sadock BJ (eds). Synopsis of Psychiatry, 8th Edition. Lippincott, Williams & Wilkins. 1998, ISBN: 0683303309 Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. McGraw-Hill Professional Publishing. 2000, ISBN: 0838577016.
Neurotransmitters - II
Glutamate in schizophrenia hypothesis - strengths:
Glutamate antagonists (PCP, ketamine) cause psychosis. Another way of stating this is that PCP an ketamine are psychotomimetic. PCP and ketamine cause some thought disorganization as well as positive symptoms, more similar to schizophrenia than dopamine agonists like amphetamine, also smell effects Data from post-mortem studies suggests that receptor systems may be altered in schizophrenia Ketmaine in animals alters gating in manner similar to impairment in schizophrenia (PPI) Current antipsychotics do NOT have glutamatergic activity, although future antipsychotics being developed appear promising (see NIMH web site) In animals appears to increase glucose function in frontal brain regions where schizophrenia seen to cause hypofrontality
Human Brain
Subjects are asked to sort each upcoming card on to one of the four piles (they are not directed but may use shape, color or number). They are told correct/incorrect. Whichever category they choose is correct for a given number of categories then is met with an incorrect response. Subjects must switch sets to get a correct response. Failure to switch sets is termed perseveration.
Schizophrenic subjects perseverate relative to normal controls, Green et al, 1992
Source: Daniel Weinberger, M.D., E. Fuller Torrey, M.D., Karen Berman, M.D., NIMH Clinical Brain Disorders Branch Division of Intramural Research Programs, NIMH
Human Brain
Dorsolateral pre-frontal Cortex appears to be Associated with poor Schizophrenic performan
GABA
Earlier studies have shown that whatever causes schizophrenia causes the prefrontal cortex area of the brain to reduce in volume. This "shrinkage" apparently causes the neurons at the front of the brain to pack more closely together, but how this abnormality could produce the symptoms of schizophrenia remains a mystery.
Tooney and Chahl are exploring this mystery by investigating how the shrinkage affects GABA neurons.
Treatment
Psychopharmacologic
Classical (= typical = conventional) antipsychotics Atypical antipsychotics Other agents
Psychosocial
Supportive therapy Social skills training Case management Working with families
Kaplan HI, Sadock BJ (eds). Synopsis of Psychiatry, 8th Edition. Lippincott, Williams & Wilkins. 1998, ISBN: 0683303309
Atypical antipsychotics
Atypical antipsychotics are serotonin-dopamine receptor antagonists They are as effective for positive symptoms and more effective for negative symptoms Clozapine is notable in particular:
It is effective in treatment refractory cases It is worse for most non-EPS side effects It has a ~1-2% risk of inducing agranulocytosis
The others (e.g., risperidone) generally produce fewer side effects than classical antipsychotics hear pamphlet
Kaplan HI, Sadock BJ (eds). Synopsis of Psychiatry, 8th Edition. Lippincott, Williams & Wilkins. 1998, ISBN: 0683303309
Other agents
Other agents may be added for augmentation purposes to the antipsychotic:
Lithium, valproate, carbamazepine Benzodiazepines
Electroconvulsive therapy (ECT) is used on occasion, especially when the patient is catatonic
Kaplan HI, Sadock BJ (eds). Synopsis of Psychiatry, 8th Edition. Lippincott, Williams & Wilkins. 1998, ISBN: 0683303309
Psychosocial
Supportive therapy
This is well supported as an adjunct to medication. (Insightoriented approaches are contraindicated.)
Case management
This greatly aids in coordination of care and optimization of treatment compliance.
P50
P50
0 50 100
300
msec
0 50 100
300
msec
Click 1
Click 2
P50 Ratio
Click 2 amp (2 V)
P50 Amplitude
4 2 Click Click 2 1
Normal Controls
Schizophrenic Patients
Reduced suppression of P50 to the second click yields a larger P50 ratio in schizophrenic patients than in normal controls
8
Click 2 / Click 1
6
4 2
Normal Controls
Schizophrenic Patients
Reason 1 P50 occurs early in auditory stimulus processing, so it may impact later processing stages when impaired P50- filtering N100-selective attention
0 50 100
300
msec
P300- evaluation
Reason 3 P50 suppression abnormalities are found in well family members P50 is hypothesized as a genetic marker
(Freedman et al., Schizophrenia Bulletin, 13, 1987)
Click 2/ Click 1
0.6
P50 Ratio
0.5 0.4
0.3 0.2
0.1 0
P50 Amplitude
Click 1 Click 2
6
4 2 0
Fluphenazine Decanoate (n = 5)
Risperidone (n = 17)
Paranoid schizophrenic patients exhibit impaired P50 suppression with attentional manipulations compared to suppression levels in a passive task
Passive Task
1.6
Click 2 / Click 1
Number Task
1.2
0.8 0.4 0.0 NC DS PS US
1.2
0.8 0.4 0.0 NC DS PS US
1.2
0.8 0.4 0.0 NC DS PS US
Anxiety Manipulation Differentially Alters P50 Suppression within Schizophrenia Oral MA Task Passive Task 2
1.5 1.0 0.5 0 NC DS PS US NC DS PS US
Preliminary Conclusions
Diagnostic subtypes of schizophrenic patients appear to exhibit distinct patterns of alteration to P50 suppression during anxiety manipulations
These results support the position that biological heterogeneity exists within schizophrenia