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Definitions
Conventional (typical) antipsychotics or "neuroleptics":
Dopamine D2 blockers,
Produce extrapyramidal symptoms (EPS)
Elevate prolactin (PRL) levels
All conventional agents are equally effective but differ in potency and side effects
Atypical Antipsychotics ("second generation" antipsychotics or dopamine-serotonin antagonists)
Share D2 and 5HT2 antagonism in common
Reduced (or absent) EPS
Minimal (or no) elevation of prolactin
Generally more effective for negative symptoms
Clozapine is the only agent clearly more effective for psychotic symptoms
Risperidone is "partially atypical"--may produce EPS at higher doses and
Atypical | Partially Atypical |
Clozapine (Clozaril)
Olanzapine (Zyprexa) Quetiapine (Seroquel) |
Risperidone (Risperdal) |
High-Potency Conventional | Mid-Potency Conventional | Low-Potency Conventional |
Haloperidol (Haldol) | Perphenazine (Trilafon) | Chlorpromazine (Thorazine) |
Fluphenazine (Prolixin) | Loxapine (Loxitane) | Thioridazine (Mellaril) |
Trifluoperazine (Stelazine) | Molindone (Moban) | Mesoridazine (Serentil) |
Thiothixene (Navane) |
Target Symptoms
Psychosis (hallucinations, delusions, disorganization)
Negative symptoms (apathy, flat affect, social withdrawal, poverty of speech)
Agitation (hyperkinesis, tension, distractibility)
Cognitive impairment (attention, memory, judgment, insight)
Basic Pharmacology of Antipsychotic Agents 1
Acute effects on dopamine systems
Conventional agents block 75-90% of D2 receptors, clozapine 40-60%
Blockade of
Delayed effects
Conventional agents increase density of post-synaptic D2 receptors (supersensitivity)
Conventional agents produce depolarization blockade in A9 (substantia nigra) and A 10
(ventral tegmental) dopamine neurons.
Atypical agents produce depolarization blockade in
All agents increase c-fos in nucleus accumbens; conventionals increase c-fos in striatum 3
Dopamine Neurons/Pathways
A9/Nigrostriatal (midbrain to neostriatum), responsible for EPS
A 10/Mesolimbic (midbrain to limbic structures) possibly associated with psychosis?
A 10/Mesocortical (midbrain to frontal and temporal cerebral cortex) negative symptoms?
Side effects with conventional agents 4-7
Side effects associated with high-potency conventional agents CEPS)
Dystonia
Akathisia
Parkinsonism
Side effects associated with low potency agents
Sedation
Hypotension
Weight gain (molindone may produce weight loss 8)
Anticholinergic symptoms (dry mouth, urinary retention, constipation, blurred vision)
Side effects unrelated to neuroleptic potency--may occur with all D2 antagonists
Hyperprolactinemia (amenorrhea, galactorrhea, sexual dysfunction)
Tardive dyskinesia
Neuroleptic malignant syndrome
Other side effects
Impaired heat regulation (hyper- or hypothermia)
Pigmentary retinopathy (thioridazine >800 mgd)
EKG changes (pimozide, chlorpromazine, thioridazine)
Drug interactions (most metabolized by cytochrome P450 2D6)
Anticonvulsants (except valproate) lower antipsychotic blood levels
Tobacco lowers antipsychotic blood levels
Erythromycin increases clozapine levels
Fluvoxamine increases clozapine levels 12
Fluoxetine (most SSRIs) increase neuroleptic levels
Tricyclic antidepressants levels increased by some neuroleptics
Extrapyramidal Side Effects (EPS)
Dystonia
Involuntary muscle contraction--may involve tongue, neck, back, eyes
Extremely uncomfortable, jeopardizes future compliance
Occurs within first four days of neuroleptic treatment
Risk factors: youth and high-potency neuroleptics
All patients under age 30 started on high potency neuroleptics should receive prophylaxis: benztropine 2 mg bid x 10 days--then taper
Treatment of acute dystonia:
benztropine 1-2 mg IM or PO
benadry125-50 mg IM or PO
diazepam 5 mg slow IV push
"Tardive dystonia" is a variant of tardive dyskinesia
Akathisia
Sensation of motor restlessness, most prominent in lower extremities
Most common with high-potency agents--dose related
Often mistaken for agitation
If present:
Switch to atypical agent or:
Lower neuroleptic dose
Beta blocker (propranolo120 mg qid)
Anticholinergic agent (benztropine 1 mg bid)
Benzodiazepine (lorazepam 0.5 mg tid)
"Tardive akathisia" variant of tardive dyskinesia
Parkinsonism
Syndrome of rigidity, tremor, bradykinesia
Bimodal age distribution (youth and old age)
Associated with high potency agents---dose related
If present:
Switch to atypical agent or:
Lower neuroleptic dose
Anticholinergic agent (benztropine 1-2 mg bid, in the elderly start with 0.25 mg)
Amantadine 100-200 mg bid
Dopaminergic agonists not recommended
Tardive dyskinesia
Late-developing choreiform movements, most commonly oral-buccal muscles
Tardive dystonia (variant)---chronic dystonic posturing
Risk factors
Old age
More than 6 months of neuroleptic exposure (5% cumulative incidence per year)
History of parkinsonian side effects
Diabetes
Affective disorders and high dose identified as risk factors in some studies (not all)
Not associated with clozapine
Reduced risk with olanzapine and risperidone?
Course
Symptoms may worsen when neuroleptic dose is decreased or with switch to atypical agent
"Withdrawal dyskinesia" usually resolves within six weeks
May worsen with anticholinergics (reversible)
Usually does not worsen with continued neuroleptic exposure
Precautions
Do not use neuroleptics if no clear benefit
Use the lowest effective dose
Monitor for TD (AIMS testing) twice-yearly 22
Warn and educate all patients who will require neuroleptics for more than 6 months
Increasingly difficult to justify use of conventional agents on this basis
Treatment
Discontinue or reduce dose of neuroleptic
Clozapine associated with increased rate of remission (especially tardive dystonia)
Vitamin E 800-1200 IU/d if duration <5 yrs (evidence for efficacy is inconsistent
Benefit of atypicals is promising but not established
Neuroleptic Malignant Syndrome (NMS)
Presentation may gradually evolve, usually in the following order:
Confusion and fluctuating levels of consciousness
Rigidity
Diaphoresis
Mutism
Autonomic instability
Hyperthermia
Elevated CPK
Atypicals may cause non-rigid NMS (controversial)
Treatment
Discontinue antipsychotic
Supportive care: hydration and temperature control
Bromocriptine 5-30 mg/day (controversial)
Wait at least 2 weeks before resuming antipsychotic
Antipsychotic Dosing
General Principles
Use a moderate, fixed dose (haloperidol 5-15 mg/d, risperidone 3-6 mg/d, olanzapine 10-15mg/d)
An adequate trial should last 4-6 wks
Use benzodiazepines prn for agitation IM or PO (eg lorazepam 1-2 mg qid) 31, 32
Blood levels
Should not substitute for clinical titration
Inconsistent evidence for haloperidol "therapeutic window" (5-15 ng/mL)
Approx 5% of patients are poor metabolizers (low P450 2D6)---may develop toxic levels
Levels useful in cases of nonresponse, noncompliance, or drug interactions
Therapeutic Ranges
Haloperidol 5-15 ng/mL
Chlorpromazine 30-100 ng/mL
Fluphenazine 0.2-2.0 ng/mL
Perphenazine 0.8-2.4 ng/mL
Clozapine >350 ng/m
First-Break Patients
Response of first-break patients:
Respond better than chronic patients
74% full remission; 12% partial response
Respond to lower doses
Haloperidol 3-10 mg/d
Risperidone 2-4 mg/d
Early treatment associated with better outcome
Treating first-break patients:
Avoid side effects (drug selection and dosing)
Prophylaxis for dystonia if using conventional neuroleptic
Develop alliance
Educate patient and family about illness and treatment
Maintenance Treatment
Relapse rates in schizophrenia | ||
Medication (n) | Placebo (n) | |
Relapse in first year | 41% (814) | 68% (189) |
Second year post discharge | 15% (500) | 65% (448) |
Depot Neuroleptics | |||
Time to peak (days) | Half-life (days) | Dosing Interval (days) | |
Fluphenazine Decanoate | 0.3-1.5 | 6-9 | 14 |
Haloperidol Decanoate | 3-9 | 21 | 28 |
Fluphenazine decanoate: conventional dose: 25 mg q 2wks
low dose: 5-6.25 mg q 2 wks
Low-dose versus conventional dose maintenance treatment 39, 40
Low and conventional doses approx, equal efficacy against relapse in first year
Low dose produces significantly less EPS and dysphoria
Conventional dose may be superior during second year for preventing relapse
Conversion to depot neuroleptic:
Requires approx 4 dosing intervals to achieve steady state
Should start with loading dose or supplement with oral medication
Always establish tolerability with oral preparation first
Haloperidol decanoate loading protocol 41.
20x daily oral dose in divided doses during first week, then decrease next two injections by 25% maintenance dose approx. 10x daily oral dose q 4 wks
Haloperidol decanoate supplementation protocol:
Administer maintenance dosing (10x daily oral dose q 4wks)
Continue 50% oral daily dose x 2 mos, 25% x 2 mos (titrate as necessary)
Atypicals
Clozapine (Clozaril)
Atypical properties
Minimal EPS
More effective than conventional agents for treatment-resistant patients
Does not elevate prolactin
Pharmacology: Dopamine systems
Weak D2 antagonist
Relatively greater D1 and D4 antagonism
Does not cause D2 receptor supersensitivity or depolarization block in A9 neurons Releases dopamine in frontal cortex
Pharmacology: Other transmitter systems
Strongly anticholinergic
Alpha adrenergic antagonist
Histaminergic (H1) antagonist
Serotonin (5HT2) antagonist
Blocks ketamine behavioral effects (NMDA receptor)
Clinical Pharmacology
Usual daily dose 300-600 mg/d (900 mg/d maximum)
Half life: 16 hrs
Metabolized by cytochromes 1A2 and 3A4
Efficacy
Effective in 30% of treatment-resistant patients at six weeks (50% at 6 mos?)
Prevents relapse
Stabilizes mood
Improves negative symptoms
Improves polydipsia & hyponatremia
Reduces hostility & aggression
May reduce suicide
Reduces cigarette smoking and substance abuse?
Adverse Effects
Sedation 39% (tolerance) Tachycardia 25%
Hypersalivation 31% (may impair swallowing)
Dizziness 19%
Constipation 14%
Nausea 11%
Headache 11%
Hypotension 9% (tolerance)
Fever 5% (usually within first 3 wks, lasting a few days)
Seizures 1-6% (related to absolute dose and rate of increase)
Weight gain 30% (diabetes)
Agranulocytosis (Granulocytes <500/mm3)
Cumulative incidence of 1.6% when taken over 52 weeks
Risk factors: Ashkenazi Jews (HLA B38, DR4, DQw3), Finns
Preservation of other cell lines (platelets and RBCs)
Maximum risk: 4-18 weeks (77% of cases)
Recovery usually within 14 days if drug stopped
No cross-sensitivity with other drugs, but avoid carbamazepine, captopril, sulfonamides and PTU
Sensitization: Do not rechallenge!
Monitoring for agranulocytosis
Weekly WBC for six months "No blood, no drug"
Pretreatment WBC should be >3500
Repeat CBC if:
WBC=3000-3500
WBC drops by 3000 from previous test
3 consecutive weekly drops
If WBC=3000-3500 & granulocytes >1500, proceed with twice-weekly WBCs
Hold drug if WBC <3000 or granulocytes <1500
Discontinue if WBC <2000 or granulocytes <1000--Do not rechallenge
After six months may monitor every 2 wks if no episodes of leukopenia
Starting clozapine
Start at 12.5 mg/d
Increase by 25 mg/d as tolerated over first week
May be added to previous antipsychotic--taper when clozapine dose >100 mg/d
BID schedule, larger dose at hs if sedation is a problem
Increase by 50 mg/d every 2-3 days during second week
Stop at 600 mg/d or when side effects develop
Risperidone (Risperdal)
Pharmacology
5HT2 and D2 antagonist
Also antagonism at D4, noradrenergic and histaminergic receptors
Half life: 24 hours (can be given once daily)
Metabolized by P450 2D6
Mean optimal dose 4-6 mg/d in chronic patients
2-4 mg/d in treatment naive patients
0.5-2 mg/d in elderly
Dose must be titrated up (start at 1-2 mg/d in non-elderly)
Efficacy (compared to haloperidol 20 mg/d in 8 wk trial)
Fewer EPS (increase with increasing dose above 6 mg/d)
More effective for negative symptoms (partly result of less EPS)
More effective for psychotic symptoms (in some treatment-resistant patients)
Side effects
Dizziness/hypotension (particularly after first dose)
Headache
Nausea/vomiting
Anxiety Rhinitis/coughing
Hyperprolactinemia
Weight gain
QT delay (usually clinically insignificant)
Olanzapine (Zyprexa)
Pharmacology
High 5HT2/D2 ratio
Anticholinergic activity in vitro, minimal effects in vivo
Histaminergic & alpha adrenergic antagonism
Metabolized by CYP 1A2 & 3A4: Half life approx. 20 hrs
Can start with 10 mg/d at hs in non-elderly
Optimal dose 10-20 mg/d (2.5-5 mg/d in elderly)
Efficacy
Antipsychotic efficacy comparable to haloperidol
More effective for negative symptoms
Substantial antidepressant effect
Antimanic efficacy compared to placebo
Side effects
Low incidence of EPS
Somnolence
Dizziness (without hypotension)
Constipation
Dry mouth
Elevation of SGPT (no evidence of hepatotoxicity)
Weight gain
Quetiapine (Seroquel)
Pharmacology
High D2/5HT2 ratio (may be effective with <60% D2 blockade) Not anticholinergic
Alpha adrenergic antagonist
Metabolized by CYP 2D6: Half life approx. 6 hrs (multiple dosing) Must titrate due to hypotension
Efficacy
Comparable antipsychotic efficacy to CPZ
More effective for negative symptoms? (not well established)
Dosing
Start at 25 mg bid (in non-elderly)
Titrate: 50 mg bid »100 mg bid »100 mg qAM & 200 mg qhs
Optimal dose: 300-750 mg/d
Side effects
Very low incidence of EPS
Postural hypotension
Somnolence
Elevation of LFTs (reversible)
Headache
Weight gain
Decreased serum T3 & T4 levels
Cataracts (in beagles--risk in humans not established, eye exams q 6 mos)
Treatment Resistance
Reassess diagnosis
Substance abuse (alcohol, PCP, stimulants)
Neurological disorders (partial complex seizures)
Psychotic depression (ECT, neuroleptic + antidepressant)
Drug toxicity/delirium (steroid psychosis, anticholinergic delirium)
Dissociative/hysterical/PTSD
Identify psychosocial stressors
Adjust neuroleptic dose
Assess compliance
Time-limited trial of higher dose, particularly if:
No or mild EPS
On drugs which induce hepatic enzymes (carbamazepine)
Olanzapine to 30 mg/d, clozapine as high as tolerated (up to 900 mg/d)
Reduce dose, particularly if:
On dose >CPZ 1 gm/day (haloperidol 20 mg/d)
Moderate or severe EPS
Haloperidol blood level
Switch neuroleptics
If failure on adequate dose of conventional agent, switch to atypicals
Atypicals differ in patterns of efficacy---each is worth consideration
Clozapine remains most effective agent
Adjunctive agents
Add risperidone (or olanzapine?) to clozapine
Add lithium (particularly if affective sxs, blood level of 0.9-1.2 for 3-5 wk trial)
ECT (catatonia, affective sxs, most effective early in course of illness)
Antidepressants (SSRIs for negative sxs; TCAs may delay response of psychosis)
Buspirone (15-30 mg/d for agitation, anxiety)
Psychosocial Interventions
Family interventions: education, realistic expectations, coping skills
Dual diagnosis treatment
Assertive community treatment (ACT)--outreach, compliance monitoring
Social skills training
Supported employment
Cognitive behavioral therapy
Relapse
Medication noncompliance
Side effects (EPS, sexual side effects, weight gain)
Lack of insight
Complexity of dosing (single hs dose, no titration, depot injections)
Stressors
Expressed emotion in family members--critical, affective arousal, enmeshed
Stressful life events
Substance abuse
Alcohol, marijuana, stimulants, PCP & ketamine
Comparisons of Atypicals
Interpreting drug trials
Last observation carried forward (LOCF)---impact of dropouts
Effect size, (clinical significance vs statistical significance)
"No difference"--difficult to interpret
Primary vs. Secondary negative symptoms
"Tran study"
Olanzapine vs risperidone 28 wk double-blind trial
Clinician adjusted dose: risperidone 7 mg/d; olanzapine 17 mg/d mean doses
Higher dropout rate with risperidone (42% vs 53%)
Comparable antipsychotic effect
Olanzapine superior efficacy for negative symptoms and depression
More EPS and hyperprolactinemia with risperidone
More weight gain with olanzapine (2.3 kg vs 4.l kg)
Efficacy for positive symptoms
Clozapine often effective in treatment-resistant patients
Risperidone more effective than haloperidol in some patients
Olanzapine not effective in rigorously defined treatment-resistant patients
Risperidone & olanzapine "comparable" to clozapine in several European studies
Quetiapine has not demonstrated superior efficacy
Clozapine still "Gold Standard"
Efficacy for negative symptoms
Conventional agents modestly improve negative symptoms but EPS result in "secondary" negative symptoms
Clozapine more effective than chlorpromazine but clozapine may not be effective in "Deficit Syndrome" patients
Deficit Syndrome: prominent, continuous primary negative symptoms
Risperidone & olanzapine more effective than haloperidol
Path analysis indicates "primary" negative symptoms improved
Weight gain
Clozapine>olanzapine>quetiapine>risperidone>haloperidol>molindone
Olanzapine-associated weight gain:
No wt gain 25%
>10 kg/yr 20%
Not dose related; tends to plateau at six months
Predictors:
Increased appetite
Good clinical response
Low baseline weight
Youth
Male gender
Start nutritional education & counseling early
Monitor serum glucose
Hyperprolactinemia
Risperidone>conventional agents>atypicals
Amenorrhea, galactorrhea, sexual dysfunction
Osteoporosis (due to secondary hypoestrogen)
Warn patients (may not volunteer symptoms)
Consider estrogen replacement (BCPs) ifamenorrhea develops
Ziprasidone
High 5HT2/D2 ratio
Half life: 10 hrs
Usual dose: 80-160 mg/d (administered bid)
Compared to haloperidol 15 mg/d
Comparable efficacy
Less EPS
Less prolactin elevation
Minimal weight gain
IM preparation (not depot)
Glutamate in Schizophrenia
Glutamate and aspartate are endogenous agonist at all glutamate receptor subtypes
Glutamate receptors are the primary excitatory receptors in the brain (GABA are inhibitory)
Glutamate receptors are involved in memory and connecting pathways relevant to models of schizophrenia Glutamate receptors also modulate dopamine activity
NMDA Receptor Antagonists (Phencylcidine & Ketamine)
Produce impressive negative symptoms and cognitive deficits in normals
Produce psychotic relapse in stable schizophrenia patients--may be blocked by clozapine
Therapeutic agents acting at the NMDA receptor complex:
Direct agonists are neurotoxic
Agonists at the glycine recognition site safely enhance NMDA receptor activity
Glycine: full agonist
D-cycloserine: partial agonist with 60% activity
Glycine and D-cycloserine both improve negative symptoms
D-cycloserine may worsen negative symptoms when added to clozapine
Some evidence suggests that antipsychotics may act in part via glycine site--relative activity may distinguish clozapine and certain atypicals
AMPA receptors
Evidence for abnormalities in schizophrenia is stronger
"Ampakines"--positive allosteric modulators
Improve memory in elderly rats
Synergistic effect with antipsychotics in methamphetamine-induced rearing model
Improves memory in normal elderly human subjects
Preliminary evidence of improved cognitive function in