Section 3.1.1

Low Potency & Low Dose Major Tranquilizers

(ANTIPSYCHOTICS)

General Description

Dopamine receptor antagonists make up the largest group of drugs known as the antipsychotics. The antipsychotics are a seemingly diverse group of drugs that have the common pharmacodynamic property of antagonizing dopamine receptors. The drugs have been referred to as neuroleptics and major tranquilizers.

The major use of antipsychotics is to treat schizophrenia, although the drugs are also used to treat agitation and psychosis associated with other mental disorders and medical conditions.

In the United States there are six classes of these antipsychotics, including the phenothiazines (like chlorpromazine, fluphenazine, thioridazine), the thioxanthenes (like thiothixene, chlorprothixene), the dibenzoxazepines (like loxapine), the dihydroindones (like molindone), the butyrophenones (like haloperidol), and the diphenylbutylpiperidines (like pimozide).

Indications for Medication

Idiopathic psychoses include schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, manic episodes, and major depressive disorder with psychotic features. The antipsychotic drugs are effective in the short-term and long-term treatment of these idiopathic psychoses: i.e., they reduce acute symptoms and prevent exacerbation.

Secondary psychoses are associated with a general medical condition such as a brain tumor or a substance related disorder. The antipsychotic drugs are effective in these secondary psychoses. In these conditions, the higher potency antipsychotics are usually safer to prescribe than the low potency antipsychotics because of their lower cardiotoxic and lower epileptogenic potential.

The administration of antipsychotics is effective in reducing the severely agitated or violent patient, although the use of sedative drugs (like benzodiazepines) may be preferable in some conditions. The antipsychotics are also effective in the agitation associated with delirium and dementia, occurring in elderly patients. Small doses of the high potency antipsychotics are usually the most effective and the safest drugs.

Clinical Guidelines

Antipsychotic drugs are remarkably safe in short-term use. If necessary, a clinician can administer these drugs without a physical examination or laboratory work-up. The major contraindications to antipsychotics include a history of serious allergic response, the possibility that the patient has ingested a drug that will interact with the antipsychotic to produce CNS depression (like alcohol, opioids, barbiturates, benzodiazepines), and the possible ingestion of a drug that might cause an anticholinergic delirium (scopolamine, possibly phencyclidine PCP).

Other contraindications to antipsychotic drugs include the presence of a cardiac abnormality, the high risk of seizures from organic or idiopathic causes, the presence of narrow angle glaucoma or prostatic hypertrophy (if an anticholinergic antipsychotic is to be prescribed), and the presence of or a history of tardive dyskinesia. Antipsychotic drugs should also be administered with caution in patients with hepatic disease. In these cases, it is best to obtain a laboratory work-up including complete blood count, liver function tests and an electrocardiogram.

The choice of a specific antipsychotic is usually based on the clinical history, psychiatric symptoms, previous medication history, and medication side effect profile and clinician preferences. High potency antipsychotics are usually favored by most clinicians because of the lower risk of cardiotoxic, hypotensive, epileptogenic and sexual side effects. High potency antipsychotic drugs, however, are associated with more neurological adverse effects.

The dose range for the group of antipsychotic drugs varies significantly. Patients absorb these medications at different rates, metabolize these medications at different rates, and achieve variable blood levels with the same dose. It is reasonable to start patients at a low dose and to titrate to a more effective range. It is important to note that maximum effects of a particular dose may not be evident for four to six weeks of treatment.

Rapid neuroleptization is the practice of administering hourly IM does of the antipsychotic medications until the desired clinical response is achieved. Several research studies have shown the benefit of waiting several hours between IM doses as this less frequent IM approach achieves equivalent efficacy for control of the psychiatric symptoms. In addition, literature articles have shown the value of adjunctive sedative medications like lorazepam (ativan) in the stabilization.

A patient with schizophrenia should continue to receive an effective dosage of the antipsychotic for at least six months after the initial improvement. For a patient who has experienced only one or two psychotic episodes, the antipsychotic drug should be gradually lowered over a three to six month period, aiming for the lowest effective dose. Some research data suggest that many patients with schizophrenia may be successfully maintained at very low doses, like haloperidol 5 mg a day.

For chronic schizophrenics with multiple psychotic episodes, the clinician may need to continue the antipsychotic drug indefinitely, although attempts to lower the drug should be attempted every several years if the patient has been clinically stable. The literature reports a number of alternative maintenance regimens, including drug holidays or "intermittent medication" treatment. However, there is evidence that indicates that drug holidays may increase incidence of noncompliance.

For chronic schizophrenics with a history of noncompliance, long-acting depot antipsychotic drugs should be considered. The two preparations are haloperidol decanoate and prolixin decanoate. Both medications may need careful titration to achieve the appropriate clinical dose, and both medications are usually administered every one to four weeks by the clinician. There is some evidence, still controversial, which indicates that depot antipsychotics may be associated with a higher incidence of tardive dyskinesia.

Adverse Effects

One generalization about the antipsychotic drugs is that the high potency drugs cause the most neurological adverse effects and that the low potency drugs cause the most non-neurological adverse effects.

The non-neurological adverse effects of antipsychotic drugs include orthostatic hypotension, peripheral anticholinergic side effects, endocrine effects, skin effects, ophthalmological effects, cardiac effects, hematological effects and jaundice.

Peripheral anticholinergic side effects are common and consist of dry mouth and nose, blurred vision, constipation, urinary retention, and mydriasis. Some patients may experience nausea and vomiting. Pilocarpine may be used in constipation with possible paralytic ileus and bethanechol (urecholine 20-40mg a day) may be used with problematic urinary retention.

The major endocrine effects cause increased prolactin which can result in breast enlargement, galactorrhea, impotence in men, amenorrhea in women, reduced sex drive, and inhibited orgasm. In particular, thioridazine is associated with decreased libido and a retrograde ejaculation.

The skin effects may include allergic dermatitis and a photosensitivity. The photosensitivity is especially common with chlorpromazine. A variety of skin eruptions - urticarial, maculopapular, petechial, and edematous - have been reported. These eruptions occur early in treatment and usually remit within several weeks.

The ophthalmological effects cause pigmentation changes to the retina and granular deposits in the anterior lens and posterior cornea. In particular, thioridazine causes an irreversible pigmentation of the retina at dose levels higher than 800mg day. Chlorpromazine is the antipsychotic most associated with the granular deposits in the lens and cornea.

The cardiac effects include possible prolongation of the QT and PR intervals, blunting of the T waves, and depression of the ST segment. In particular, thioridazine has marked effects on the T-wave. Patients with cardiac histories should be carefully evaluated before receiving low potency antipsychotics.

The hematological effects usually include a common, but not serious leukopenia, often with a white blood cell count (WBC) of around 3,500. Agranulocytosis is a rare but life-threatening problem seen with all antipsychotic drugs, but probably occurring most frequently with chlorpromazine and thioridazine. The incidence is only 1 in 500,000 (well below the risk with clozapine).

The antipsychotic drugs may interfere with pregnancy tests. Antipsychotics should be avoided in the first trimester of pregnancy, unless the benefits outweigh the risk. Antipsychotic use in the second and third trimesters of pregnancy is unlikely to cause fetal malformations. Behavioral disturbances in the neonate are possible. There is no clear contraindication to breast feeding in mothers who are taking phenothiazines though haloperidol and phenothiazines pass into breast milk.

The neurological adverse effects of antipsychotic drugs include epileptogenic effects, sedation, central anticholinergic effects, and neuroleptic-induced acute dystonia, neuroleptic-induced parkinsonism, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and neuroleptic malignant syndrome.

Epileptogenic effects are caused by a slowing and increased synchronization of the EEG with a reduction of the seizure threshold. The risk of inducing a seizure with an antipsychotic drug warrants consideration when the patient already has a seizure disorder or an organic brain lesion.

Central anticholinergic effects may include severe agitation, disorientation, hallucinations, seizures, high fever and dilated pupils. Stupor and coma may ensue. Treatments of these adverse effects consist of discontinuing the antipsychotic drug, close medical supervision and possibly physostigmine (Antilirium) 2mg by slow IV infusion.

Neuroleptic-induced acute dystonia occurs in approximately 10% of patients, usually in the first few hours or days of treatment. Dystonia can involve the neck (spasmodic torticollis or retrocollis), the jaw (forced opening resulting in a dislocation or trismus), tongue (protrusions, twisting), the eyes (oculogyric crisis with the eyes moving upward and lateral), or the entire body (opisthotonos).

Neuroleptic-induced acute dystonia are common in young men (less than 40 years old) but they can occur in either sex. Prophylaxis with anticholinergics or related drugs usually prevents the development of dystonia. Treatment with IM anticholinergics or IV/IM diphenhydramine almost always relieves the symptoms.

Neuroleptic-induced parkinsonism occurs in approximately 15% of patients, usually within the 5-90 days of the initiation of treatment. Symptoms may include muscle stiffness, cogwheel rigidity, shuffling gait, stooped posture and drooling. A pill-rolling tremor is rare but a coarse tremor may occur more frequently. Rabbit syndrome (a focal, perioral tremor) can occur late in treatment.

Neuroleptic-induced parkinsonism occurs most frequently in women and in patients older than age 40. The syndrome can be treated with anticholinergics, amantadine, or diphenhydramine. Although amantadine may have fewer of its own side effects, it may be less effective at reducing muscular rigidity.

Neuroleptic-induced acute akathisia is a subjective feeling that causes patients to be agitated, pace relentlessly, stand up and sit down continually and feel dysphoric. Akathisia can appear at any time during treatment. It is probably under-diagnosed because its symptoms can be mistakenly attributed to psychosis, agitation or poor cooperation.

With neuroleptic-induced acute akathisia, the dose of antipsychotic drugs should be reduced and treatment with anticholinergics or amantadine should be attempted. In the psychiatric literature, there is data which supports the effectiveness of propanolol (Inderal) 30-120mg a day, benzodiazepines and clonidine.

Neuroleptic-induced tardive dyskinesia is a delayed effect of the antipsychotic drugs, rarely occurring until after at least six months of treatment. The syndrome consists of abnormal, involuntary, irregular choreoathetoid movements of the muscles of the head, limbs and trunk. Perioral movements are most common and include darting, twisting, and protruding movements of the tongue with chewing, lip puckering and facial grimacing.

All of the antipsychotics have been associated with causing tardive dyskinesia. The longer patients are taking the antipsychotics, the more likely they are to develop the tardive dyskinesia. Women are more affected than men are. Patients over the age of 50 with brain damage and patients with mood disorders seem to be a higher risk for developing this condition. The incidence increases to 3-4% after five years of treatment and rises to approximately 20% in chronic patients.

The three basic approaches to tardive dyskinesia are prevention, diagnosis and management. Prevention is best achieved by treating the patient with the lowest effective dose. Patients should be checked regularly for the appearance of abnormal movements, preferably by using a standardized rating scale (see specific section on tardive dyskinesia). When abnormal movements are detected, a differential diagnosis should be fully considered.

With the development of tardive dyskinesia, consideration should be given to reducing or stopping the antipsychotic drug, if at all possible. Consideration should also be given to substituting an atypical antipsychotic. Other drugs (lithium, carbamazepine, valproic acid, benzodiazepines) may be necessary to reduce both the psychotic symptoms and the movement disorder.

Neuroleptic malignant syndrome is a life-threatening complication of antipsychotic treatment with a variable time of onset during treatment. Symptoms include muscular rigidity and dystonia, akinesia, mutism, obtundation, and agitation. The autonomic symptoms include hyperthermia (up to 107F), sweating, increased pulse and blood pressure. Laboratory findings may reveal increased white blood cell count, blood creatinine phosphokinase, liver enzymes and myoglobin.

Neuroleptic malignant syndrome usually evolves over 24-72 hours. The untreated syndrome may last 10-14 days. Men are affected more than women are. The mortality rate is between 15-25%. The treatment is the immediate discontinuation of the antipsychotic drug, medical support to cool the patient, and the monitoring of vital signs and renal output. Dantrolene may reduce muscle spasms and bromocriptine may also prove beneficial in this treatment.

Drug-Drug Interactions

The antipsychotic drugs have a wide range of drug-drug interactions with antacids, anticholinergics, anticonvulsants, antidepressants, antihypertensives, central nervous system depressants and many other drugs.

Antacids and cimetidine (Tagamet) may reduce the absorption of the antipsychotic, reducing its efficacy.

Anticholinergics may also reduce the absorption of antipsychotics. In addition, the anticholinergics and some antidepressants may increase the anticholinergic activity of the antipsychotics, causing toxicity.

The phenothiazines may decrease the metabolism of phenytoin, resulting in toxicity from phenytoin. Barbiturates may increase the metabolism of antipsychotics and the antipsychotics may lower seizure threshold.

Tricyclic antidepressants and antipsychotics may decrease each other's metabolism, resulting in elevated plasma levels of both medications. The anticholinergic, sedative and hypnotic effects of these medications may be additive. Fluoxetine may dramatically increase the level of antipsychotics.

Antipsychotics may inhibit the uptake of guanethidine and may also inhibit the hypotensive effects of clonidine and alpha-methyldopa. Conversely, antipsychotics may have an additive effect on other hypotensives.

Antipsychotics potentiate the CNS depressant effects of sedatives, antihistamines, opiates, opioids and alcohol. This is particularly problematic in patients with any impaired respiratory status.

The co-administration of antipsychotics with lithium may result in symptoms similar to those of lithium toxicity and neuroleptic malignant syndrome. There is no clear data to indicate a higher incidence of those syndromes with co-administration of lithium and antipsychotics.

Cigarette smoking may decrease plasma levels of antipsychotic drugs, reducing their efficacy.

Pharmacology
Select dosage and pharmacologic parameters of antipsychotics

Antipsychotic Agent

Approx. equiv. dose (mg)

Adult daily dosage range (mg)

Sedation

Extra-pyramidal symptoms

Anti-cholinergic effects

Ortho-static hypo-tension

Weight gain

Thera-peutic plasma con-centration (ng/ml)

Conventional (typical) agents

Phenothiazines-aliphatic

Chlorpromazine

100

30 to 800

+++

++

++

+++


30-500

Promazine

200

40-1200

++

++

+++

++



Phenothiazines-piperazine

Fluphenazine

2

0.5-40

+

+++

+

+


0.5-3.0

Perphenazine

10

12-64

++

++

+

+


0.8-1.2

Trifluoperazine

5

2-40

+

+++

+

+



Phenothiazines-piperidine

Mesoridazine

50

30-400

+++

+

+++

++



Thioridazine

100

150-800

+++

+

+++

+++



Thioxanthenes

Thiothixene

4

8-30

+

+++

+

++


2-57

Phenylbutyl-piperadine

Butyrophenone

Haloperidol

2

1-15

+

+++

+

+


5-12

Diphenylbutyl-piperadine

Pimozide

0.3-0.5

1-10

++

+++

++

+



Dihydroindolones

Molindone

10

15-225

++

++

+

+



Dibenzepines

Dibenzoxazepines

Loxapine

15

20-250

+

++

+

+



Novel (Atypical) agents

Dibenzodiazepines

Clozapine

50

300-900

+++

+

+++

++

++


Thienbenzo-diazepine

Olanzapine


5-20

+++

+

+++

++

++


Dibenzothiazepine

Quetiapine


50-800

++

+

0

++

+


Benzisoxazoles

Risperidone


4-16

+

+ /++

0

+

+


+++ high incidence ++ moderate incidence + low incidence

At > 10mg/day, Risperidones' EPS profile is similar to conventional antipsychotics

Reference: Facts and Comparisons Jan. 2000

Atypical Antipsychotic Agents Adverse Reactions (%)

Adverse Event

Clozapine (n=842)

Olanzapine (n=248)

Quetiapine (n=510)

Risperidone (n=401)

Cardiovascular

Chest pain/angina

1

4

-

2-3


Hypertension

4

-

-

-


Hypotension

9

2

-

-


Postural hypotension

-

5

7

-


Tachycardia

25

4

7

3-5







Central Nervous System

Aggressive reaction

-

-

-

1-3


Agitation

4

23

-

22-26


Akathesia

3

5

-

-


Amnesia

-

2

-

-


Anxiety

1

9

-

12-20


Confusion

3

-

-

-


Disturbed sleep/nightmare

4

-

-

-


Dizziness

19

11

10

4-7


Euphoria

-

2

-

-


Fatigue

2

-

-

-


Headache

7

17

19

12-14


Insomnia

2

20

-

23-26


Personality Disorder

-

8

-

-


Restlessness

4

-

-

-


Rigidity

3

2

-

-


Seizures

3

-

-

-


Slurred Speech

1

2

-

-


Somnolence/Drowsiness

39

26

18

3-8


Stuttering

-

2

-

-


Syncope

6

-

-

-


Tremor

6

4

-

-

Dermatologic

Dry skin

-

-

-

2-4


Rash

2

2

4

2-5

Gastrointestinal

Abdominal pain

-

4

3

1-4


Constipation

14

9

9

7-13


Diarrhea

2

-

-

-


Dry mouth

6

7

7

-


Dyspepsia

4

-

6

5-10


Nausea

5

-

-

4-6


Toothache

-

-

-

2


Vomiting

3

-

-

5-7

Geniturinary

Premenstrual syndrome

-

2

-

-

Hematologic/Lymphatic

Leukopenia/decreased WBC/neutropenia

3

-

-

-

Metabolic/Nutritional

Increased appetite

-

2

-

-


Peripheral edema

-

2

-

-

Musculoskeletal

Arthralgia

-

5

-

2-3


Twitching

-

2

-

-

Respiratory

Coughing

-

5

-

3


Dyspnea

1

-

-

1


Pharyngitis

-

5

-

2-3


Rhinitis

-

10

3

8-10


Sinusitis/nasal congestion

1

-

-

1-2


Upper respiratory infection

-

-

-

3

Miscellaneous

Asthenia

-

-

4

-


Back pain

1

4

2

2


Fever

5

5

2

2-3


Muscle pain

1

4

-

-


Sweating

6

-

-

-


Visual Disturbances

5

8

-

1-2


Weight gain

4

6

2

-

Reference: Facts and Comparisons Jan. 2000

Data are pooled from several sources and are not necessarily comparable