Pharmacotherapy With Anti Pharmacotherapy With Anti Psychotic MedicationsPsychotic Medications

Danesh A. Alam, M.D.Danesh A. Alam, M.D.Fellow, Psychopharmacology and ResearchFellow, Psychopharmacology and Research

Psychiatric Clinical Research CenterPsychiatric Clinical Research CenterUniversity of Illinois at ChicagoUniversity of Illinois at Chicago

Rauwolfia Serpentina:Rauwolfia Serpentina: The First Herbal AntipsychoticThe First Herbal Antipsychotic

The first antipsychotic, Rauwolfia Serpentina, was prescribed by physicians in ancient India over two millennia ago.

The ancient Ayurvedic pharmacopoeia describes the

use of R. Serpentina in the treatment of “insanity”

(oonmaad in Sanskrit). “onmaad” is a description of

psychosis by the Ayurvedic physician Chakra (circa

1000 BC) as an “abnormal condition of the mind,

wisdom, perception, knowledge, memory, character,

creativity, conduct, and behavior.”

Rauwolfia Serpentina:Rauwolfia Serpentina: The First Herbal AntipsychoticThe First Herbal Antipsychotic

In 1931, Sen and Bose described the tranquilizing and antihypertensive effects of R. Serpentina root extracts. (Rauwolfia Serpentina: a new Indian drug for insanity and high BP. Indian Medical World 1931:11:194-201).

In 1952, reserpine was isolated from Rauwolfia extracts. Arvid Carlsson (Sweden) discovered the central nervous

system neurotransmitter properties of dopamine while studying the mechanism of action of reserpine. Reserpine works by depleting cells of dopamine, thus, reducing brain dopaminergic activity.

Anti Psychotic DrugsAnti Psychotic Drugs

Chlorpromazine, 1952

Developed as an anti-autonomic agent

~20 anti-psychotic drugs available (US)

1st generation or typical i.e.-

chlorpromazine, haloperidol, fluphenazine

etc. vs. 2nd generation or atypical i.e.-

risperidone, olanzapine, quetiapine etc.

Schizophrenia Schizoaffective

disorder Mood Disorder with

psychosis Dementia with

psychosis Delirium Delusional disorder Psychosis secondary to

a non-psychiatric medical disorder

Developmental disability with psychosis and/or aggression Tourette’s disorder, Huntingdon’s chorea, intractable hiccups Acute Mania Augmentation in Major Depression and Bipolar disorder

AntipsychoticsAntipsychoticsCommon IndicationsCommon Indications

Positive symptoms• Hallucinations• Delusions

Negative symptoms (deficit syndrome)• Primary• Secondary

DysphoriaNeuroleptic-induced deficit syndrome (NIDS)

Cognitive symptoms• Dissociated thinking• Disorganization of thoughts• Attentional impairments

Schizophrenia: Symptom domainsSchizophrenia: Symptom domains

Dopamine hypothesis • Increased release• Increased sensitivity of postsynaptic receptors• Dopamine receptor subtypes

Serotonin Norepinephrine Gamma-aminobutyric acid (GABA) Glutamate

• N-methyl-D-aspartate (NMDA)• Phencyclidine (PCP)

Peptides• Neurotensin• Cholecytoskin (CCK)• Somatostatin (SOM)

Antipsychotics: Mechanism of ActionAntipsychotics: Mechanism of Action

Dopamine Receptors

Plethora of DA receptors exist 5 pharmacological subtypes:

D1, D2, D3, D4 and D5

D2 Receptor: Most extensively studied Stimulated by agonists for treatment of Parkinson's Blocked by antagonists for treatment of Schizophrenia

Dopamine Pathways (4)

NIGROSTRIATAL DOPAMINE - projects from substantia nigra to basal ganglia - controls movements

MESOLIMBIC DOPAMINE -projects from midbrain ventral tegmental area to nucleus accumbens- delusions, hallucinations, pleasurable sensations

MESOCORTICAL DOPAMINE -projects from midbrain ventral tegmental area, sends axons to limbic cortex - mediates (+) and (-) symptoms

TUBEROINFUNDIBULAR DOPAMINE -projects from hypothalamus to anterior pituitary gland - controls prolactin secretion

22ndnd Generation or Novel Antipsychotics Generation or Novel Antipsychotics

Clozapine (Clozaril)

Risperidone (Risperdal)

Olanzapine (Zyprexa)

Quetiapine (Seroquel)

Ziprasidone (Geodon)

Diminished extrapyramidal side effects (EPS)

Minimized risk for tardive dyskinesia (TD)

No hyperprolactinemia

Beneficial for treatment of refractory patients

Improved negative symptoms

Improved cognitive/mood symptoms

2nd Generation/Novel/Atypical? 2nd Generation/Novel/Atypical? ProfileProfile

Advantages Disadvantages

Treatment of refractory patients Agranulocytosis

Negative symptoms Seizures

Minimal risk of EPS or TD (?) Weight gain

No prolactin increase Orthostasis

Tachycardia

Sedation

Sialorrhea

Constipation

The Role of ClozapineThe Role of Clozapine

Refractory PsychosisRefractory Psychosis

Change anti-psychotic after adequate dosage trial

Consider noncompliance and depot injections

Antipsychotic combinationse.g., addition of neuroleptic

Adjunctive medications

Long-Acting (or Depot) AntipsychoticsLong-Acting (or Depot) Antipsychotics

Esters synthesized from the hydroxyl group of active

base and long-chain fatty acids

Dissolved in sesame oil vehicle

Ester is hydrolyzed by plasma esterases after

injection and slow release into systemic circulation

Css achieved in about 3 months

Terminal elimination half-life: 3 weeks

Depot Antipsychotics: Potential Depot Antipsychotics: Potential AdvantagesAdvantages

May benefit treatment-refractory patients on oral

preparations

May decrease noncompliance

Bioavailability approaches 100%

Lower and more predictable plasma drug levels with

clinically equivalent doses of oral preparations

Longer duration of action

Transition from Oral to Depot Transition from Oral to Depot AntipsychoticsAntipsychotics

Oral supplement during the vulnerable period

Use a high (or loading) depot dose initially

Increased frequency of injections early in

course of depot therapy

Antipsychotic Combinations IAntipsychotic Combinations I Proposed Rationale: Proposed Rationale:

Extensive unpublished clinical experience? (difficult to examine without bias)

Differences in pharmacological action between typicals and atypicals? (poor understanding of required neurochemical action)

Extensive published evidence? (no controlled trials to date. Most published studies examine addition of typical to clozapine)

Antipsychotic Combinations IIAntipsychotic Combinations II Temporary Situations: Temporary Situations:

“Lead-In” combinations - typicals supposedly having more rapid action during acute emergency)

“Top-Up” combinations - addition of typical to overcome acute exacerbation

“Switch-Over” combinations - when switching between antipsychotics

Adjunctive TreatmentAdjunctive Treatment

Anticholinergics

Benzodiazepines (anxiety, akasthisia)

Carbamazepine (effective in acute episode; long

term studies not done)

Lithium (excitement, overactivity, euphoria)

Valproic acid (psychosis?)

Propranolol (akasthisia, psychosis)

Atypical antipsychotics represent a significant departure from the conventional neuroleptics

These agents can also adversely affect several systems

The most critical to consider are the neurological, hematological, cardiovascular, and endocrine

Other problems occur due to their cholinergic or sexual adverse effects

Drug interactions can also occur

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Major PointsMajor Points

Acute EPS

• Dose-related EPS

• Primary vs. secondary negative symptoms

Neuroleptic malignant syndrome

Tardive dyskinesia (other tardive syndromes)

Seizures (e.g., clozapine)

Sedation, headache, withdrawal syndrome

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics NeurologicalNeurological

Preferential DA blockade in meso-cortico-limbic pathway

5HT2 ‚ 5HT1c, or 5HT3 blockade

High 5HT2/DA2 blockade ratio

Low D2 occupancy

Rapid release of bound antipsychotic from receptor due to

loose binding (clozapine and quetiapine)

Anticholinergic effects

Antihistaminergic effects

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Low EPS Risk of Atypical Low EPS Risk of Atypical

AntipsychoticsAntipsychotics

MaximumMaximum MinimumMinimum

Acute EPSAcute EPS

Adverse Effects of AntipsychoticsAdverse Effects of Antipsychotics

NEUROLEPTICS RISPERIDONE OLANZAPINE CLOZAPINE

(DOSE-RELATED ZIPRASIDONE

QUETIAPINE

Neuroleptics

Clozapine-induced agranulocytosis

• Management

Stop agent

Reverse isolation; supportive measures

GCSF (cytokines, filgastrim)

• Rechallenging strategies

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics HematologicalHematological

Related to both alpha adrenergic and muscarinic effects

• Hypotension

• Tachycardia

Arrhythmogenic potential possible with all antipsychotics

• QTC interval

QTC prolongation

QTC dispersion

• Torsade de Pointes

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics CardiovascularCardiovascular

Most common with:

Clozapine

Olanzapine

Quetiapine

Low-potency neuroleptics

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics AnticholinergicAnticholinergic

Inconsistent effects on hormone-related activity• Pituitary (prolactin, menstrual dysfunction)

• Thyroid

Antagonism of DA receptors in the pituitary can result in increased prolactin levels, possibly causing:

• Lactation/breast engorgement

• Gynecomastia

• Sexual dysfunction (decrease in sexual interest reversed by bromocriptine)?

• Anxiety and mood disturbance?

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics NeuroendocrineNeuroendocrine

anti-Serotonin (5HT2)

anti-dopamine (impaired erection, inhibited orgasms)

anti-norepinephrine (reduced intensity of orgasm)

anti-cholinergic (impaired erection)

anti-histamine (loss of libido, impaired erection)

Adverse Effects of AntipsychoticsAdverse Effects of Antipsychotics Sexual Adverse EffectsSexual Adverse Effects

Dosage reduction, avoidance of

antimuscarinic agents

Switching to another agent

Various drugs may be helpful

(e.g., sildenafil, yohimbine (NE),

cyproheptadine (5HT2 antagonist )

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Sexual Adverse Effects: ManagementSexual Adverse Effects: Management

Recognized problem since chlorpromazine• More common with atypicals

• Altered metabolism vs. satiety vs. activity Diabetes mellitus associated with typicals and

atypicals

• More problems managing DM

• New-onset cases of DM;• Ketoacidosis

Long-term weight-associated concerns • Elevated triglycerides and cholesterol• Heart disease and hypertension

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Weight Gain: General IssuesWeight Gain: General Issues

-1

0

1

2

3

4

5

6

Allison DB et al. Am.J.Psychiat;156;1686-1696, 1999

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Mean weight gain after 10 weeks (kgs)Mean weight gain after 10 weeks (kgs)

Increased calorie consumption Decreased calorie use (less activity, sedation) Mechanism of weight gain is unknown

• Genetic contribution• Dopamine blockade (e.g. amantadine)• Noradrenergic blockade (e.g., amphetamines)• Serotonin blockade (e.g., fenfluramine;

5HT2c, 2a, 1a ) • Histamine blockade (e.g., antihistamines)• Glucose and insulin dysregulation

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Weight Gain: MechanismWeight Gain: Mechanism

Dietary changes

• Patient education about causes

• Strategies to reduce food intake

Exercise

Screening for related health problems

• Diabetes

• Hypertension

• Serum cholesterol

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Weight Gain: Treatment OptionsWeight Gain: Treatment Options

Retinitis pigmentosa (e.g., thioridazine)

Cataracts (e.g., quetiapine?)

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics OcularOcular

Cataracts in chronic dog studies

No cataracts seen in two 1-year monkey studies

Lens changes in a long-term clinical trial were

comparable to control group (haloperidol)

Across all controlled clinical trials, the proportions of

patients with lens changes were similar in quetiapine,

haloperidol , and placebo groups

Periodic ocular examinations are recommended

Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Ocular Assessments in Quetiapine TrialsOcular Assessments in Quetiapine Trials

Summary of Antipsychotic TreatmentSummary of Antipsychotic Treatment

Fewer adverse effects with atypicals – greatly reduces adverse effects burden– clozapine is an exception

Major decrease in risk of EPS and TDProlactin increase and other risks are lowerWeight gain is a problem – varies across atypical class

Trivia

Antipsychotic that cause less weight gain: molindone & ziprasidone

droperidol- only approved for IV use in anaesthesia

Pimozide approved for use in Tourettes only

Clozapine- reduces suicide in schizophrenia

All antipsychotics lower the seizure threshold, 2nd generation <1%

Other meds that cause ac. Dystonia, akathesia, parkinsonian sideeffects and NMS- prochorperazine (compazine), metoclopramide, promethazine (Phenergan).