Schizophrenia Flashcards
Is schizophrenia seen more in males or females?
Equal prevalence but onset tends to be earlier in males.
What are the comorbid conditions often associated with schizophrenia?
HTN DM Cardiac STDs Substance abuse Smoking
What is the etiology of schizophrenia
Genetic susceptibility (multiple alleles) Environmental exposure Fetal disturbance (ie., infection, hypoxia) leads to abnormal neuron migration
What is the course of illness for schizophrenia?
Most deterioration in psychosocial functioning occurs within first 5 years
Early treatment predicts better long-term outcomes
Majority of patients experience at least 1 relapse
What are the positive sx of schizophrenia?
Added to a normal patient's presentation Hallucinations Delusions Bizarre behavior paranoia or suspiciousness disorganization
What are the negative sx of schizophrenia?
Taken away from a normal patient's presentation Avolition Alogia Affective flattening Asociality Anhedonia Attentional impairment
What are the cognitive sx of schizophrenia?
Difficulties with concentration memory
executive functioning
Decision making
What types of hallucinations are there?
Auditory Visual Tactile Olfactory Gustatory
What is a fixed, false belief held despite negative evidence, and not consistent with cultural norms
Delusion
What are the types of delusions?
Grandiose
Persecutory
Referential
Somatic
What are the types of disorganization with though disorder?
Normal Loose associations Tangential Circumstantial Flight of ideas
How is schizophrenia diagnosed via the DSM-IV-TR
A.Two (or more) of the following, each present for a significant portion of time during a 1-month period: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms
B. For a significant portion of the time since onset of the disorder, 1 or more major areas of functioning such as work, interpersonal relations, or self-care are significantly below the level of prior to onset
C.Continuous signs of the disorder for at least 6 months. This must include at least 1 month fulfilling criterion A (unless successfully treated). This 6 months may include prodrome or residual symptoms
D.Exclusions
Schizoaffective or mood disorder has been excluded
Disorder is not due to a medical disorder or substance abuse
If history of pervasive developmental disorder is present, there must be symptoms of hallucinations or delusions present for at least 1 month
What are the subtypes of schizophrenia?
Paranoid Type Disorganized Type Catatonic Type Undifferentiated Type Residual Type
What is the DSM-IV diagonistic criteria for schizoaffective disorder?
A.Period of illness where there is a Major Depressive, Manic, or Mixed episode concurrent with symptoms concurrent with symptoms that meet Criterion A for Schizophrenia
B.During the same of illness, there have been delusions or hallucinations for at least 2 weeks in the absence of prominent mood symptoms
C.Mood symptoms are present for a substantial portion of the total duration of the active and residual periods of the illness
D.Not due to the effects of a substance or general medical condition
What are the subtypes of schizoaffective disorder?
Bipolar Type
Manic or Mixed Episode +/- Major Depressive Episode
Depressive Type
If the mood disturbance only includes Major Depressive Episodes
What are the dopamine pathways?
Nigrostriatal
Mesolimbic
Mesocortical
Tubero-infundibular
What is the role of the nigrostriatal in the dopamine pathway?
Regulates motor movement
Blockade -> Extrapyramidal Movements (EPS)
What is the role of the mesolimbic in the dopamine pathway?
Hyperactivity -> Positive Symptoms (hallucinations, delusions)
What is the role of the mesocortical in the dopamine pathway?
Hypoactivity -> Negative Symptoms, Cognition Issues
What is the role of the tubero-infundibular in the dopamine pathway?
Inhibits prolactin, thermoregulation
Blockade -> hyperprolactinemia
How does dopamine antagonism affect schizophrenia?
Improvement of positive symptoms
EPS
Hyperprolactinemia
Minimal improvement of negative symptoms
What are the treatment options for schizophrenia?
First Generation Antipsychotics (FGA)
Conventional agents, neuroleptics, or typical antipsychotics
Second Generation Antipsychotics (SGA)
Atypical antipsychotics
What are the phenothiazine first generation antipsychotics?
Chlorpromazine (Thorazine®) Thioridazine (Mellaril®) Mesoridazine (Serentil®) Perphenazine (Trilafon®) Trifluoperazine (Stelazine®) Fluphenazine (Prolixin®)
What are the non-phenothiazine antipsychotics?
Thiothixene (Navane®)
Haloperidol (Haldol®)
Loxapine (Loxitane®)
Molindone (Moban®)
What are the low potency first generation antipsychotics and what is important about them?
Less potent D2 antagonism
More Ach, alpha-antagonism, sedation
Chlorpromazine, thioridazine, mesoidazine
What are the medium potency first generation antipsychotics and what is important about them?
Moderate D2 antagonism as well as receptor selectivity
Perphenazine, loxapine, molindone
What are the high potency first generation antipsychotics and what is important about them?
More potent D2 antagonism
Less Ach, alpha-antagonism, sedation
Fluphenazine, haloperidol, thiothixene, trifluoperazine
What are the second generation antipsychotics (atypicals)?
Aripiprazole (Abilify®) Clozapine (Clozaril®) Olanzapine (Zyprexa® Quetiapine (Seroquel®) Risperidone (Risperdal®) Ziprasidone (Geodon®)
Antipsychotics- MOA
Postsynaptic DA: 5 receptors
D1 and D5 activate adenylyl cyclase
D2 , D3 and D4 inhibit adenylyl cyclase
Every antipsycholic blocks D2 receptors
Typical Antipsychotics
Mesolimbic DA block: reduces Positive Symptoms
Not so good for Negative or Cognitive Symptoms
Atypicals: also block 5-HT>DA
Good for Positive Symptoms
Possibly better for Negative and Cognitive Symptoms
5-HT2 antagonists release dopamine from inhibition and decreases EPS
What other receptors are antipsychotics known for blocking?
Also block adrenergic, cholinergic and histamine-binding receptors
Unknown what role these actions have in alleviating symptoms of psychosis
Undesirable side effects result of binding these receptors
How well the drug acts at the D2 receptor is correlated with what?
How well the drug works
What is D2 occupancy?
D2 occupancy is related to:
Clinical response (threshold 65%) (positive sx go away at 65%)
Prolactin elevation (threshold 72%)
EPS and akathisia (threshold 78%)
Is the therapeutic window narrow or wide
Therapeutic window is narrow
In principle -> therapeutic response is possible (but not probable) without EPS, akathisia, or prolactin level
What is Dx2 and 5-HT2 occupancy?
Depending on dose, drugs work at “typical” levels of D2 occupancy
However, when D2 occupancy is >80%, lose some of its “atypical” features
What does olanzapine saturate?
Olanzapine saturates 5-HT2 receptors; therefore, at clinical doses, muscarinic M1 and histaminergic H1 also likely saturated
Ziprasidone
5-HT2 occupancy exceeds D2 occupancy
Estimated steady-state 5-HT2 occupancy up to 90%
Estimated steady-state D2 occupancy up to 75%
Clozapine
the “mother” of all atypical antipsychotics
Advantages over typical antipsychotics
Lack EPS, lack prolactin elevation, efficacy in refractory pts, greater efficacy on suicidality, efficacy against negative symptoms?
5-HT2 occupancy >80 occupancy
Inability to occupy >70% D2…works at levels of D2 occupancy that alone would not cause response
What is the transient occupancy hypothesis with quetiapine?
Transiently high D2 occupancy appears sufficient to obtain and maintain antipsychotic response
400mg Seroquel->57% D2 occupancy at 3 hrs->20% D2 occupancy at 9 hrs.
What are the benfits of atypical (2nd generation) antipsychotics?
Efficacy for positive symptoms, clozapine effective for treatment resistant positive symptoms
Possible enhanced efficacy for negative and cognitive symptoms
Low incidence of tardive dyskinesia and EPS (look like PD patients)
Minimal or no effect on prolactin at usual doses (except risperidone)
How should you dose antipsychotics?
Start with the lowest dose possible.
Divide doses to minimize SE
Prophylactic anticholinergics with high potency
Antipsychotics- Side effects (neurological)
Neurological (Extrapyramidal) DA block
Occur with chronic use of typical neuroleptics
Low incidence with atypical neuroleptics
Antipsychotics- Side effects (non-neurological)?
Non-Neurological (Low Potency medications)
Histaminergic: Sedation, Wt gain
Anticholinergic: Peripheral & Central
Alpha-Adrenergic: Orthostasis, EKG
Endocrine-Sexual: PRL, 5-HT
Hematologic: Agranulocytosis (clozapine black box warning)
Eye & Skin: retinopathy, photosensitivity
Seizure threshold: lowered
Liver: cholestatic jaundice
Are neurological effects worse with typicals or atypicals?
Typicals
Are non-neurologic side effects worse with typicals or atypicals?
Atypicals
What are the extrapyramidal Sx (EPS) of anipsychotics?
- Acute Dystonias
- Parkinson-like symptoms (blocking of DA receptors in nigrostriatal pathway)
- Akathisia (motor restlessness)
- Tardive Dyskinesia (inappropriate postures of neck, trunk, and limbs)
- Neuroleptic Malignant Syndrome
What is a muscle spasm in the face, neck, trunk, eye, or larynx?
Acute dystonia
What is the treatment for acute dystonia?
Treatment: Benadryl 50 mg IM (IV 25-50 for laryngospasm), Cogentin (benztropine (generic)) 1-4 mg IM
Prevention reduces incidence to 5%
Low dose
Benztropine 1 mg / every Haldol 5 mg
What is antipsychotic-induced parkinsonism?
Incidence 50-75% with high potency Rigidity Bradykinesia: mask face-gait problems Resting Tremor Flexed Posture Dif Dx. with flat affect
What is the tx for antipsychotic-induced parkinsonism?
Tx: Cogentin (benztropine), Artane 2 mg bid-tid
What is a subjective feeling of reslessness and involved unable to sit still and pacing?
Akathisia
What is used to tx akathisia?
Tx: Propranolol 30-90 mg/d (not in asthma or diabetes), Klonopin 1 mg bid
*Beta blocker
What is slow choreo-athetotic movements and oro-facial movements?
Tardive dyskinesia
What is used to tx tardive dyskinesia?
Tx?: Vit E 1600 U/d, Clozapine low risk
What are the risk factors of tardive dyskinesias and when are they more seen?
Risk factors: elderly women, mood D/O, diabetes
More associated with typical (1st gen) antipsychotics
What is neuroleptic malignant syndrome (NMS)?
Medical Emergergency, mortality 20% (now 4%)
1. FEVER>100.4F / 37.5C
2. SEVERE EPS: lead-pipe/cogwheel rigidity, sialorrhea, oculogyric crisis
3. AUTONOMIC, DYSFUNCTION: BP fluctuations, tachycardia, tachypnea, diaphoresis
Also: Alt. consciousness, delirium, leukocytosis (>15.000 WBC), CPK > 300, seizures, arrhythmias, mioglobinuria, ARF
What are the risk factors associated with NMS?
Risk factors: multiple IM injections, high dose, rapid increase of dose agitation, dehydration, heat, lithium use
What is the treatment for NMS?
Stop ALL Antipsychotics
Dif. Dx: fever & delirium
Dantrolene (muscle relax) 1-3 mg/kg/day NTE 10 mg/kg/d
Bromocriptine (DA Agonist) 5 mg tid-qid
Supportive Tx:
IV fluids, antipyretics, cooling blankets, close cardiac & renal monitoring
What are the antiemetic effects?
Block D2 receptor of chemoreceptor trigger zone of medulla
Exception is thioridazine
What are the antimuscarinic effects?
Thioridazine, chlopromazine, clozapine, olanzapine
Anticholinergic effects include blurred vision, dry mouth, sedation, confusion, inhibit GI and urinary tract smooth muscle constipation and urinary retention
What are the other effects that are seen with low potency and atypicals?
Alpha-adrenergic blockade causes orthostic hypotension, light-headedness
Poikilothermia (body temp varies with environment)
D2 blockade in pituitary->increased prolactin release
More common with high potency and typicals
Chlorpromazine and clozapine antagonize H1 receptor->sedation
Typical antipsychotics- Pharmacokinetics
t1/2 approx 24 hrs (hs or bid) SE limit the amount given in one dose Peak plasma level: 2-4 hrs (po) 30 min (IM) Takes 5-7 days to steady-state Mainly CYP2D6 metabolism Tolerance but little dependence IM depot (slowly over time release) available in fluphenazine and haloperidol form outpt tx or noncompliance Slow release over 3 weeks 30% develop extrapyramidal symptoms
Clozepine (Clozaril)
Atypical antipsychotic Weak D1=D2 block, high 5-HT2 block (5-HT2/D2 = 20/1) alpha1, alpha2, H1, M1 Tx Res. Schizophrenia, mood stabilizer Effective in Negative and Positive Sx, low EPS, low TD
What is the biggest side effect of clozapine?
AGRANULOCYTOSIS (1%), 80% in 1st 4 mo. (BLACK BOX WARNING FOR AGRANULOCYTOSIS)
Potentially fatal in 1-2%
If WBC<1,000 stop & do not re-start
Do not use with Carbamazepine or other bone marrow suppressors
Clozapine- Side effects
Agranulocytosis Sedation Dizziness, orthostatic hypotension Hypersalivation Weight Gain Lower Seizure Threshold
Risperidone
Atypical antipsychotic
low EPS at doses <6 mg/d; Treat agitation in the elderly; Elevates PRL; minimal sedation
Ziprasidone
Atypical antipsychotic
need bid, tid
t1/2 5 hrs; low EPS; contraindicated in pts with cardiac arrhythmias; minimal weight gain
Olanzapine (Zyprexa®)
Atypical antipsychotic
positive and negative Sx, low EPS, sedation, wt gain, mood stabilizer
Quetiapine (Seroquel®)
Atypical antipsychotic
need bid, low EPS, sedation, hypotension
Aripiprazole (Abilify®)
Atypical antipsychotic
Low EPS
What commonly occurs with atypical neuroleptics?
Weight gain
What commonly occurs with typical neuroleptics?
Parkisonian effects
What is the maintenence of medications for patients with schizophrenia?
2+ episodes should receive maintenance therapy for at least 5 years
High dose maintenance therapy preferred in preventing relapse
