Antipsychotic Medications in the Primary Care Practice

Angelo Potenciano, M.D.

Antipsychotic Medications

• Antipsychotics have been around since 1951

• Approximately 40 APs in the market globally

• 15 are Typical APs / “Neuroleptics

• 21 are Atypical APs – 9 are in the U.S.

Antipsychotics in the Primary Care Setting

• Lieberman (2002) noted that PCP Rx

Of APs has increased 18-20% since 1996

PCPs treat a variety of psychiatric disorders including depression, anxiety, bipolar disorders, sleep disorders, psychosis,

and behavioral problems assoc. with dementia, and delirium

Reasons Why PCPs Are Vital in the Treatment of Psychiatric

Patients• Not enough psychiatric services available • Psychiatric symptoms arising from medical d/o or

during the course of treatment• Patients are more comfortable seeing their PCP• Stable Patients who require maintenance meds

History of Antipsychotics

• 1891 – Paul Ehrlich and Paul Guttman pioneered the use of Methylene Blue –a phenothiazine derivative in the Tx of Malaria

• 1890s- noted the tranquilizing and antidepressant effects

• Became the lead compound in the development of Chlorpromazine

History of Antipsychotics

• 1951 –French surgeon, Henry Leborit used Chlorpromazine as a sedating agent

• 1952 John Delay and Pierre Deniker treated 38 schizophrenics with CPZ 75-100mg/day/IM

• Dramatic improvements in thinking and emotional symptoms and overall behavior

History of Antipsychotics

• 1954-1975 development of typical ApsThioridazine – Mellaril

Haloperidol- Haldol

Trifluoperazine- Stelazine

Perphenazine- Trilafon

Fluphenazine- Prolixin

Molindone-Moban

Pimozide

History of Antipsychotics

• 1980s-Janssen developed Risperidone

• The earliest Atypical APs

• Followed the LSD model of psychopathology- Risperidone-antagonized effects of LSD

History of Antipsychotics

• 1989 Clozapine was approved by the FDA

In treating treatment-resistant schizophrenia

1971 introduced in Europe but was withdrawn in 1975 due to angranulocytosis

Atypical Antipsychotics

Aripiprazole- Abilify Quetiapine- Seroquel

Asenaphine- Saphris Ziprasidone- Geodon

Clozapine- Clozaril

Iloperidone- Fanapt

Lurasidone- Latuda

Olanzapine- Zyprexa

Risperidone- Risperdal

Mechanism of Action of Antipsychotics

• Dopamine antagonist- D1-4 R

• Typical APs / Neuroleptics- D2R (tightly bound)

• Atypical Aps- D1 & 2R (loosely bound or rapid dissociation), 5HT 2A and 5HT2C

Mechanism of Action

• D2R antagonism – EPS (akatishia, dystonia, parkinsonism, tardive dyskinesias)

• Rapid dissociation from DA receptor- less EPS risk

• 5HT binding(2A) – mood and cognitive effects, decreased DA blockade

Clinical Uses of Antipsychotics

FDA Approved Indications

1. Psychotic symptoms due to Schizophrenia or Schizoaffective disorder

2. Mood disorders: Bipolar disorder and Major depressive disorder

Clinical Uses of Antipsychotics

“Off-Label” or Non-FDA Approved

1. Psychotic symptoms of various etiology- substance-induced, dementia, delirium

2. Behavioral problems secondary to developmental disorders (autism, ADHD), dementia, delirium, other neurological disorders

3. Sleep disorders

4. Anxiety disorders

Antipsychotics and Schizophrenia

-First-line psychiatric treatment

-psychotic symptom reduction in 1-2 weeks

-almost 80% response rate (partial – good)

-choice is based on cost, side effects / safety, dosing

Clinical Uses of Antipsychotics

• FDA Approved Indications Schizoaffective Disorder- Iloperidone (Fanapt) Treatment-Resistant Schizophrenia (failure to respond

after 6 weeks of trials with 2-3 different antipsychotic- Clozapine (Clozaril)

Clinical Uses of Antipsychotics

• FDA Approved Indications

Bipolar Disorder: Asenapine, Aripiprazole, Lurasidone, Olanzapine, Quetiapine, Risperidone, Ziprasidone

Antipsychotics and Bipolar Disorders

FDA Approved Indications

Bipolar disorder-Mixed or Manic Episode:

Asenapine, Aripiprazole, Olanzapine, Quetiapine, Risperidone, Ziprasidone

Bipolar Disorder- Depressive episode:

Lurasidone, Olanzapine-Fluoxetine (symbyax), Quetiapine

Monotherapy or adjunctive therapy with Lithium or valproate

Antipsychotics and Bipolar Disorder

• Clinical Advantages:

1. does not require blood levels (Valproate, lithium)

2. safer in patients with co-morbid substance abuse, liver/kidney diseases

3. Safer in overdoses / toxicities

Injectable Antipsychotics

Acute agitation associated with Schizophrenia or Bipolar Disorder: Haloperidol, Olanzapine, Ziprasidone

Antipsychotics Use in Children

Bipolar disorder in children and adolescents (aged 10-17) (Monotherapy): Quetiapine, Risperidone

Schizophrenia in Adolescents (aged 13-17):

Aripiprazole, Risperidone

Behavioral issues associated with Autistic d/o (irritability, aggression, self-injurious beh.,temper tantrums, rapidly changing moods):

Risperidone, Aripiprazole

Antipsychotics and Depressive Disorders

Treatment-Resistant Depression:

Olanzapine-Fluoxetine Combination

Adjunctive / Augmentive Treatment of Major Depression: Aripiprazole, Quetiapine XR

Off-Label Uses of Antipsychotics

• Behavioral issues associated with Dementia and Delirium: agitation/ aggression, psychosis, sleep disturbances, anxiety, confusion

• Increasing consensus in the efficacy of APs• Atypical APs-less EPS and anticholinergic effects• Haloperidol (low doses) as safe and effective as

atypical APs

Antipsychotics for Dementia

Clinical Antipsychotic Trials of Intervention

Effectiveness-Alzheimer’s Disease 2008

(CATIE-AD): Effectiveness of Olanzapine, Quetiapine, Risperidone in improving anger, aggression, paranoia / hostile suspiciousness but NOT overall functioning, care needs, and quality of life

Antipsychotics for Delirium

• Haloperidol- antipsychotic of choice (Society of Critical Care Medicine 2007)

• Risk of EPS and Cardiac Conduction Changes

• Olanzapine, Quetiapine, Risperidone- as efficacious, with less side effects, quicker improvement, less agitation, better sleep patterns

Antipsychotics in the Elderly

• 1.6-1.7 times risk of death in patients taking APs

• Duration of treatment: 10 weeks

• Common causes: sudden death, CV-Heart failure, infectious (pneumonia)

• 1.7-2 times risk of CVAs in dementia patients taking Antipsychotics

Off-label Uses of Antipsychotics

• Sleep disorders—sedative effects of Aps can promote sleep

• Most sedating APs: Olanzapine, Quetiapine,

Chlorpromazine, Thioridazine

Metabolic and EPS side effects are concerns in long-term use

Off-label Uses of Antipsychotics

• Anxiety disorders / symptoms—OCD, GAD, Panic Disorders

• tranquilizing / anxiolytic effects of most APs used in combination with SSRIs or Benzos. –Mostly inconclusive study results

• May be more useful in patients with co-morbid disturbances or psychosis

Tourette’s Disorder

• Risperidone and Pimozide—best evidence

• Aripiprazole-promising data; lower risk for side effects

Side Effects

• EPS-Parkinsonian, Dystonia, Akatishia,Tardive Dyskinesia

• Elderly patients are at higher risk for EPS and TDs –develops more readily and are more persistent

• Mostly seen in use of Conventional APs or neuroleptics and Risperidone

Side Effects

• Metabolic: weight gain, hyperglycemia, hyperlipidemia

Most likely to cause Metabolic side effects: Olanzapine, Quetiapine, Risperidone

Less Likely: Ziprasidone, Asenapine, Lurasidone

Side Effects

• Prolonged QTc Interval and Sudden Death:

• Most APs will carry this risk (Haloperidol, Droperidol, Pimozide)

• Highest risk:

Thioridazine

Ziprasidone (no evidence yet to suggest that this leads to sudden death)