pharm, lecture 4- antipsychotics, mood stabilizers, stimulants

schizophrenia

1. severe, persistent mental illness

2. impacts cognition & functioning

3. usually emerges during adolescence or early adulthood

cause of schizophrenia

1. genetic

2. neurodevelopmental factors

3. environmental factors

pathophys of schizophrenia

1. disrupted synaptic pruning

2. altered connectivity in prefrontal, temporal, and hippocampal regions

3. dysregulation of dopaminergic neurotransmission

treatment focus for schizophrenia

1. symptom management

2. no cure

comorbid conditions of schizophrenia

1. obesity

2. type 2 DM

3. smoking

positive symptoms

excessive or distortion of normal functions

positive symptoms associated with schizophrenia

1. hallucinations

2. delusions

3. disorganized speech

4. disorganized/catatonic behavior

negative symptoms

diminished or absent normal functions

negative symptoms of schizophrenia

1. flat affect

2. alogia

3. anhedonia

4. avolition

5. social withdrawal

alogia

significant reduction in speech or verbal output

avolition

lack of motivation

cognitive symptoms

thinking/processing deficits

cognitive symptoms of schizophrenia

1. impaired attention

2. working memory deficit

3. executive dysfunction

4. impaired processing speed

5. poor insight/judgement

catatonia

range of motor, cognitive, and behavioral disturbances

retarded or stuporous catatonia

1. mutism

2. stupor- immobility, unresponsiveness

3. posturing/ waxy felxibility

4. negativism- resists instructions

excited catatonia

1. excessive, purposeless motor activity

2. agitation/impulsivity

3. echolalia- mimicking words

4. echopraxia- mimicking movements

malignant catatonia

1. catatonic signs plus autonomic instability- fever, tachycardia, HTN, diaphoresis

2. life threatening

periodic catatonia

1. rare

2. alternating episodes of stupor and excitement- may recur in cycles

secondary catatonia

due to medical/neuro causes

DSM-5 criteria for schizophrenia

1. two or more of the following are present for significant period of time for one month

2. delusions

3. hallucinations

4. disorganized speech

5. grossly disorganized or catatonia

6. negative symptoms

what is common in patients with schizophrenia?

impaired level of functioning in areas of work, interpersonal relations, or self- care

mesolimbic pathway

1. dopaminergic pathway

2. involved in pleasure

3. euphoria from drug misuse

hyperactivity of mesolimbic pathway leads to...

1. hallucinations

2. delusions

3. aggression/ hostility

mesocortical pathway

dopaminergic pathway

what does mesocortical pathway regulate?

1. cognition

2. executive functioning

3. emotions

4. affect

deficit of dopamine associated with mesocortical pathway leads to:

negative symptoms

nigrostriatal pathway

dopaminergic pathway

what does nigrostriatal pathway regulate?

movement

deficiency in dopamine associated with nigrostriatal pathway leads to:

1. Parkinson's/ pseudoparkinsonis

2. rigidity

3. akinesia/bradykinesia

4. tremor

5. akathisia

6. dystonia

hyperactivity of dopamine associated with nigrostriatal pathway leads to:

1. chorea

2. dyskinesia

3. tics

4. tardive dyskinesia

tardive dyskinesia

chronic blockade of D2 receptor

tuberoinfundibular pathway

dopaminergic pathway

what does the tuberoinfundibular pathway regulate?

prolactin

what inhibits release of prolactin?

normal dopamine function

deficiency of dopamine function associated with tuberoinfundibular pathway

1. gynecomastia

2. galactorrhea

3. amenorrhea

4. other sexual dysfunction

first generation low potency antipsychotics

1. chlorpromazine

2. thioridazine

first generation medium potency antipsychotics

1. loxapine

2. perphenazine

first generation high potency antipsychotics

1. fluphenazine

2. haloperidol

3. pimozide

4. thiothixene

5. trifluoperazine

which first gen high potency antipsychotic is very high risk for extrapyramidal effects?

haloperidol

which first gen high potency antipsychotic is very high risk for QT prolongation?

haloperidol

MOA of first gen antipsychotics

1. block receptors for dopamine (D2 receptor inhibition)

2. also anti- histamine, alpha 1, and muscarinic

therapeutic use of first gen antipsychotics

1. suppression of acute psychotic episode symptoms

2. used especially for + symptoms

3. reduce risk for relapse

onset of action for first gen antipsychotics

1. 1-2 days- initial effects

2. 2-4 weeks- substantial improvement

3. several months- full effect

there is more incidence of what side effects with first gen antipsychotics than second gen?

extrapyramidal symptoms and NMS

which first gen antipsychotic is preferred for initial therapy ?

haloperidol- high potency

what side effects are less prevalent with use of haloperidol?

1. sedation

2. orthostatic hypotension

3. anticholinergic effects

use of haloperidol

acute psychosis

which side effects are less prevalent with use of chlorpromazine and thioridazine- first gen low potency antipsychotics?

extrapyramidal symptoms

which side effects are more prevalent with use of chlorpromazine and thioridazine- first gen low potency antipsychotics?

1. sedation

2. hypotension

3. anticholinergic effects

extrapyramidal symptoms

1. acute dystonia

2. parkinsonism

3. akathisia

4. tardive dyskinesia

signs and sx of acute dystonia

painful, prolonged, abnormal spasms of muscles of tongue, face, neck, back

signs and sx of parkinsonism

1. bradykinesia

2. mask-like facies

3. tremor

4. rigidity

5. shuffling gait

6. drooling

7. cogwheeling

8. stooped posture

signs and sx of akathisia

1. compulsive restless movements

2. anxiety

3. agitation

signs and sx of tardive dyskinesia

involuntary movements of body and extremities

treatment for acute dystonia

diphenhydramine or benztropine- both anticholinergic

treatment for Parkinsonism

diphenhydramine or benztropine- both anticholinergic

treatment for akathisia

1. reduce dose

2. switch meds

3. propranolol

4. benztropine

treatment for tardive dyskinesia

1. 1st discontinue offending agent

2. VMAT 2 inhibitors

3. benzodiazepine

when does acute dystonia usually present with use of first gen antipsychotics?

hours to days of starting/increasing dose

when might acute dystonia be life threatening?

if the airway is involved- can lead to asphyxia

what is the most common EPS symptom?

Akathisia

when does akathisia usually present with use of first gen antipsychotics?

hours to weeks of starting/increasing dose

when does parkinsonism usually present with use of first gen antipsychotics?

weeks to months, even years later

when does tardive dyskinesia usually present with use of first gen antipsychotics?

months to years later

benztropine

anticholinergic

MOA of benztropine

1. blocks acetylcholine receptors

2. restores dopamine-ACH balance in CNS

indications for benztropine

treating dystonia, akathisia, parkinsonism caused by antipsychotic meds

side effects of benztropine

1. dry mouth

2. blurred vision

3. urinary retention

4. constipation

vesicular monoamine transporter type 2 inhibitors (VMAT2)

end in - benazine

MOA of VMAT2 inhibitors

inhibit VMAT2 which decreases reuptake of dopamine into vesicles

when are VMAT2 inhibitors indicated?

tx for tardive dyskinesia

side effects of VMAT2 inhibitors

1. sedation

2. fatigue

3. restlessness

4. dry mouth

what should patients on VMAT2 inhibitors be monitored for?

suicidality or worsening depression

warnings for use of VMAT2 inhibitors

1. suicidality

2. depression

3. QT prolongation

First gen antipsychotic major adverse effect?

neuroleptic malignant syndrome (NMS)

timing for NMS associated with first gen antipsychotics?

1. more common with high potency first gen antipsychotics

2. typically occurs 1 to 30 days after start of medication or dose escalation

signs and symptoms of NMS

1. lead pipe rigidity

2. high fever >105 degrees F

3. sweating

4. agitation

5. confusion

6. seizure

complications of NMS

1. autonomic instability

2. dysrhythmias

3. BP fluctuations

4. rhabdomyolysis

treatment for NMS

1. discontinue offending agent

2. antipyretics, hydration, benzos

3. dantrolene- muscle relaxant

4. bromocriptine- dopamine agonist

5. after tx- wait 2 weeks before initiation of antipsychotic

most common presenting symptom of NMS

fever

adverse effects of first gen antipsychotics

1. anticholinergic effects

2. orthostatic hypotension

3. prolonged QT

4. sedation

5. neuroendocrine effects

6. seizures

7. sexual dysfunction

8. agranulocytosis

black box warning of first gen antipsychotics

increased risk of mortality when used to treat dementia-related psychosis in older adults

second gen antipsychotics (atypical)

1. aripiprazole

2. clozapine

3. olanzapine

4. quetiapine

5. ziprasidone

MOA of second gen antipsychotics

blocks receptors for dopamine (D2) and serotonin (5-HT)

therapeutic use for second gen antipsychotics

1. suppression of acute psychotic episode symptoms

2. help + and - symptoms

3. reduce risk for relapse

4. bipolar mania

5. adjunct for depression

onset of action for second gen antipsychotics

1. 1-2 days- initial effects

2. 2-4 weeks- substantial improvement

3. several months- full effect

why are second gen antipsychotics preferred over first gen?

less EPS symptoms

most common adverse drug reactions associated with second gen antipsychotics?

1. weight gain, metabolic syndrome

2. hyperprolactinemia- risperidone

3. agranulocytosis- cloazpine

when can metabolic syndrome occur with use of second gen antipsychotics?

can be within weeks

clinical findings of metabolic syndrome

1. weight gain

2. diabetes

3. dyslipidemia

what can metabolic syndrome lead to?

CV events and premature death

what should be monitored if metabolic syndrome occurs with second gen antipsychotics?

1. weight

2. HgbA1c/ fasting glucose

3. lipids

ALL second generation antipsychotics have what black box warning?

increased risk of mortality when use to treat dementia-related psychosis in older adult patients

which antipsychotic is more effective than other agents?

clozapine

who is clozapine reserved for?

1. pt that has not responded to other antipsychotics

2. pt who has had significant SE/medical risks

what is required to prescribe clozapine?

REMS program

what should be monitored for patients on clozapine?

1. WBC and ANC for agranulocytosis

2. check weekly for 6 months

3. then every 2 weeks for additional 6 months

4. then monthly

what WBC should you stop cloazpine?

<3000

what WBC should you permanently stop clozapine?

<2000

black box warning for cloazpine

1. rare but can be fatal- myocarditis

2. sx- unexplained fatigue, dyspnea, tachypnea, chest pain, palpitations

3. if occurs- stop med and dont use again