Antipsychotic Drugs (major tranquilizers)
While these medications all have sedating and calming effects, their major effect is to reduce psychotic thinking and behavior. In general, other drugs are safer and more effective if sedation is the entire aim.
Traditional Antipsychotic Medications:
All of the older or traditional antipsychotic medications have the same mechanism of action; they all work by blocking sites in the brain that are usually stimulated by a neurotransmitter called dopamine. This dopamine blockade accounts for many of the side effects of the medications as well as for their therapeutic action.
All of the traditional antipsychotic medications are equally effective, but they vary in potency. That is, they all do an equally good job, but it takes different amounts of medication to be equally effective. A 100 mg. dose of Thorazine is equal in effectiveness to approximately 2 mg of Prolixin.
The drugs do have somewhat different side effects although this is a matter of degree rather than kind. High potency medications like Haldol and Prolixin have more muscle side effects (referred to as extrapyramidal side effects, or EPSE) but less sedation and less anticholinergic side effects (dry mouth, blurred vision, constipation). Also, for unclear reasons, a particular consumer may respond better to one medication than another. Another way that different antipsychotic medications differ is in cost!
Atypical Antipsychotic Medications:
There are now several newer or "atypical" antipsychotic medications. Clozapine was the first of these new generation antipsychotic medications to be marketed. Respiridone was releasted in February 1994, and at least two other, olanzapine and sertindole are now undergoing clinical research trials and could be marketed in the next year or two. We now know there are at least 5 different dopamine receptors in the brain. Traditional antipsycotic medications like haloperidol seem to work by blocking the D2 receptor. The atypical antipsychotic medications block different dopamine receptors, and some of the serotonin receptors.
All of these atypical antipsychotic medications have fewer extrapyramidal (muscle) side effects than traditional meds. It is likely that these meds are also less likely to cause tardive dyskinesia (a movement disorder). Finally, they may be more effective than the older meds. Clozapine is effective in many consumers who have not responded to other antipsychotics. Clozapine also seems much more effective in "negative symptoms" (lack of motivation, flat affect) than traditional medications. The research is less complete on the other atypical medications, but it is hoped they will share clozapine's increased effectiveness.
When to use antipsychotics:
Psychosis: When a psychotic consumer first takes an antipsychotic medication, there is an immediate calming effect that makes many consumers more comfortable and decreases management problems. There is also a direct antipsychotic effect that takes several days or weeks to be seen. Many consumers with a clear diagnosis of schizophrenia who become psychotic and agitated after discontinuing their medication can be "rapidly tranquilized" with Prolixin or Haldol 5 - 10 mg liquid concentrate, pills or by injection every hour until they calm down. This is often done in an emergencyć room and is an effective way of avoiding hospitalization in consumers who are already known to the mental health system. Recent research suggests that in most consumers, moderate doses are as effective in decreasing psychotic symptoms and cause fewer side effects than very high doses. Traditionally it has been said that with very agitated consumers one of the more sedating phenothiazines (e.g., Thorazine) might be preferred, while a paranoid consumer who is likely to be very sensitive to "being drugged" might respond better to one of the less sedating meds like Haldol or Prolixin. My own preference is to use high potency, less sedating medications in almost all cases. The high potency antipsychotics have an advantage with very agitated consumers because it is possible to safely and rapidly administer a much larger equivalent dose of medication with Haldol or Prolixin than with Thorazine.
Schizophrenia: The majority of consumers with schizophrenia will have a relapse if they discontinue their antipsychotic meds. It used to be thought that all consumers with schizophrenia needed to be on maintenance antipsychotic meds for many years. Recently, there has been increasing interest in decreasing the consumer's long term exposure to medication, and research has supported the idea of low dose and targeted dose strategies, even with consumers with long-term illness. The low dose research has suggested that many consumers can do well with much lower doses of antipsychotic medication than are traditionally used, especially if these consumers are monitored closely and they are given additional medication during periods of relapse. The targeted medication research has demonstrated that at least some consumers with schizophrenia do not need to be kept on maintenance antipsychotic medication at all. The use of medication can be limited to a few weeks during periods of relapse for those consumers who do well for periods of time off medication, and who are willing to go back on medication when necessary.
Most consumers with schizophrenia do not relapse immediately if they discontinue antipsychotic medication. Research suggests that a consumer with schizophrenia who discontinues medication has around a 10% chance of relapsing the first month. Of those who do not relapse during the first month off medication, approximately 10% will relapse the second month and so on, with around 10% of the remaining consumers relapsing every month they are off medication. This means that some consumers will go many months before relapsing, and that a brief period of stability while off medication does not mean that medication is no longer needed.
Manic depression-manic phase acute: Antipsychotics are used in moderate to large dosages (e.g., start Prolixin 5 mg. three times a day and increase as needed up to 30-60 mg) to control consumers initially until lithium has had time to become more effective. It used to be felt that antipsychotic medications were the most effective way to rapidly control the behavior of manic consumers. Increasingly, benzodiazepines, either alone or along with an antipsychotic medication, allows for behavioral control with fewer side effects than if an antipsychotic medication were used alone.
Organic brain syndromes (OBS): Antipsychotic medication is often of benefit in very low dosages (Haldol 2 mg. or Mellaril 25 mg. h.s. [before bed]); use only after the medical work-up of the OBS is completed and the diagnosis is firmly established. Antipsychotics can help to control both problematic behavior and emotional lability in some of these OBS consumers. More is not better. Dose of medications should be kept low. Higher doses can cause confusion and cause behavioral problems to become worse especially in elderly consumers or those with dementia.
Delusional depression: Consumers who are psychotically or delusionally depressed initially respond much better to the combination of antipsychotic plus antidepressant medications than to antidepressants alone. Once the consumer has begun to respond, the antipsychotic can be tapered and then discontinued, leaving the antidepressant for maintenance therapy. Except in very rare cases, antipsychotics should not be used as maintenance medication for consumers who have been psychotically depressed but who are not currently psychotic. Also, some very agitated depressed consumers will have a faster feeling of relief and have a faster reduction in their agitation if low dose antipsychotic medications are initially used along with the antidepressants. Again, these meds should be used for short periods of time in these depressed consumers.
Non-agitated, non-delusional depressed consumers are often made worse by antipsychotic medications, especially by the more sedating ones such as Thorazine. Any consumer can feel depressed if antipsychotic medications are used in too high a dose.
Six important cautions
1. A diagnosis needs to be made first. Meds should not be given just because a consumer is upset, or even because he/she is psychotic. It is necessary to first become clear about what is going on. Delirium needs to be ruled out. Delirium can easily be confused with psychosis but can be distinguished by a careful mental status exam given by the doctor. Consumers with delirium are often disoriented and almost always have a memory impairment.
2. Medical illness or drug intoxications (substance abuse) need to be considered as these may present as psychosis.
3. A medication history needs to be obtained (what meds has the consumer taken in the past in what dose with what effect). If a consumer has previously had a good response to a particular medication, it makes sense to restart that same drug.
4. Follow treatment by picking out specific symptoms to target. Auditory hallucinations might a target symptom for one consumer, disorganized thinking for another consumer, and social withdrawal for yet another. Medications can be adjusted according to target symptoms and side effects.
5. More is not necessarily better. Too much of these meds can cause an increase in side effects without necessarily being any more effective. These side effects can make the consumer's clinical symptoms worse, and at times drug side effects can be difficult to distinguish from the illness being treated. These drugs all take days to weeks to work and too rapid escalation of drug dose because the consumer has not responded in the first 24 hours can lead to inappropriately high doses being used. At the same time, using too low a dose of medication can prolong the period of psychosis. There are few clear rules for arriving at the optimum dose for each consumer, other than to listen to what the consumer says and observe how the consumer responds.
6. Actively look for side effects. These meds are often uncomfortable to take and all have significant side effects. Actively monitoring and treating side effects will help consumers feel more comfortable, and will also help increase the consumer's willingness to continue taking the medications.
Potential Side Effects of Antipsychotic Medications:
Side effects of the antipsychotic meds can be divided into those that are common, uncomfortable, but not life threatening, and those that are rare but can be very dangerous or lead to permanent difficulties. (Many people are reluctant to discuss side-effects with consumers for fear of scaring them. In addition, doctors rarely discuss side-effects for lack of time. The result is that when consumers do develop side-effects, they become scared because they haven't previously been discussed. They may then discontinue the medicine. It is my opinion that side-effects should be discussed openly with consumers and put in context of the benefits of the medicines which, in most cases, outweighs the side-effects. -ed.)
Serious, Potentially Permanent Side Effects are rare
1. Blood dyscrasias: Many consumers put on these drugs have a partial block on production of certain blood elements, usually white cells and platelets. This is usually of no clinical significance and within a few days the system is back to normal. Occasionally the white blood count continues to decrease slowly (leukopenia) in a dose related reaction without other symptoms-this must be followed closely if it occurs and sometimes requires switching to a different medication. If this temporary block is relatively complete and does not revert to normal the rapid decrease in white cells and/or platelets quickly becomes life threatening. Such a complete block is very rare, but is relatively more common with low potency, high dose drugs (Thorazine and Mellaril). It is much more common with clozapine (Clozaril), a very new antipsychotic medication.
Problems with the production of white blood cells usually occurs within 6-8 weeks of starting a new medication, and is more common in debilitated consumers. Symptoms include weakness, high fever, chills and a sore throat. An MD should be called and a CBC (complete blood count) ordered immediately. Outcome depends on how rapidly diagnosis is made. If the consumer has a blood dyscrasia, all medication must be stopped immediately.
2. Neuroleptic malignant syndrome (NMS): This is a rare, potentially fatal side effect that usually occurs very shortly after starting antipsychotic medications and is marked by very high temperature and muscle stiffness. Consumers can rapidly die from hyperthermia (high temperature above 105 degrees) if not rapidly and vigorously treated. Any consumer who complains of an increased temperature and muscular rigidity should be evaluated for this.
3. Temperature regulation: All of these medications can interfere with the person's normal temperature regulation mechanisms in hot weather. Consumers on these medications, especially Thorazine, are much more subject to potentially fatal heatstroke.
4. Cardiovascular effects: Use with some caution in people with a history of heart disease although this is usually not a serious problem. Mellaril increases the time for the heart to repolarize slightly more than the other phenothiazines. It should probably not be used in consumers with certain kinds of irregularities of heart beat. Sudden death has been reported as a very rare side effect of all of these drugs.
5. Eye problems: Blurred vision is a common, reversible side effect from all of these medications, especially the high dose medications like Thorazine and Mellaril. This is an "anticholinergic" side effect and is made worse by other anticholingeric medications, including medications used for extrapyramidal side effects such as Cogentin or by antidepressants such as Elavil. The blurred vision goes away when the medication is discontinued.
Cataracts are a rare but more serious side effect, especially of long term Thorazine use. Mellaril has been reported to cause the deposition of the pigments in the retina of the eye that can lead to blindness. This has only been reported in consumers taking over 800 mg./day for a lengthy period of time.
6. Seizures: All of these medications lower the seizure threshold. Seizures are a rare possibility in people taking these medications, but are something to consider especially in consumers who already have difficult to control epilepsy. Some of these medications, such as clozapine, are much more likely to cause seizures than other antipsychotic medications.
7. Jaundice: (consumer turns yellow because of accumulation of bilirubin secondary to liver disease) is now very rare. Ir usually develops after 2-4 weeks of treatment.
Common, Uncomfortable, But Usually Temporary or Reversible Side Effects of Antipsychotic Medications
8. Toxic side effects: include drowsiness, feeling "drugged," sluggish, unmotivated. They are more or less present in anyone taking these meds. They are usually dose related and can sometimes be controlled by changing dosages, giving most of the medication at night or switching medication. They are often worse with Thorazine than with the high potency antipsychotics. Consumers may become partially tolerant to these symptoms over time. Drug induced or drug excerbated depressions are also possible.
9. Psychotoxic effects including depression, depersonalization, dysphoria (sadness), akinesia, confusion and somatic delusion.
As you can see, antipsychotics can make things worse as well as better depending on how used.
10. Autonomic side effects: The most common anticholinergic side effects include dry mouth, blurred vision and constipation. Other autonomic side effects can include orthostatic hypotension (sudden drop in blood pressure when the consumer suddenly stands up) which can cause some transient dizziness and in extreme cases, cause the consumer to fall down. All of these side effects are worse with low potency drugs like Thorazine and Mellaril.
11. Endocrine Effects: Weight gain is sometimes a major problem. There is supposed to be no weight gain with molindone (Moban). All of these drugs can interfere with menstruation and can cause lactation (even in men).
12. Sexual dysfunction: Impotency or retrograde ejaculation (erection and ejaculation is normal but semen is pushed backwards into the bladder instead of the penis) can be a problem in some men. Both men and women describe decreased sexual desire.
13. Skin reactions: Includes rashes, itching, some swelling. Symptoms usually begin 1-5 weeks after beginning treatment. Thorazine is the most common offender. These rashes are uncomfortable, but usually not dangerous.
14. Photosensitivity reactions: Skin can become very sensitive to sunlight. Again, Thorazine is most common drug involved.
Muscle effects (worse with Haldol and Prolixin)
Extrapyramidal (muscle) side effects are common and are a frequent reason why consumers refuse to take medications, and can add tremendously to many consumer's discomfort. They are usually treatable and except for tardive dyskinesia all disappear when drugs are discontinued. TD has no reliable treatment, and may be permanent even after the antipsychotic medications are stopped.
Extrapyramidal side effects are much less frequent with the new antipsychotic medication, clozapine. In addition, clozapine does not appear to cause TD.
15 Dystonia: Symptoms include sudden, often dramatic, spasms of muscles of head, neck, lips and tongue. Tilted head, slurred speech or eyes deviated up or to one side are also common. Dystonias can be very frightening and at times are dismissed as bizarre behavior rather than a drug side effect. Dystonias usually occur hours or days after the medication is started or the dose is increased. Easily treated with anticholinergic drugs eg. Cogentin 1-2 mg. orally or injected in muscle, or Benadryl 25 mg. intraveneously for rapid relief.
16. Pseudoparkinsonism: Usually consists of muscular rigidity, mask-like face, stiff walk with loss of normal arm swing and a shuffling gait. These consumers often have a coarse, 3 per/sec tremor that is worse at rest and gets better with activity. Usually begins after 3 weeks or so of treatment.
17. Akathisia: Akathisia is a common, very uncomfortable and often unrecognized side effect that is one of the frequent reasons that consumers discontinue their medication. Characterized by constant pacing, moving of hands or feet, a feeling of nervousness. When asked, consumers can often distinguish this motor restlessness from anxiety, and say things like "it feels like my motor is running all of the time." Akathisia often becomes more severe if the person is otherwise anxious, and can become somewhat better if the person is more relaxed. This can become very confusing since akathisia can easily be confused with anxiety in the first place. Akathisia can also be confused with an exacerbation of the underlying psychosis. Some consumers find that caffeine makes it worse. It is usually a late appearing side effect that usually occurs 5-14 days after beginning meds.
18. Akinesia: is frequently overlooked and can be difficult to separate from the illness for which the drug is being prescribed. It is manifested by loss of spontaneity in facial expression or gesturing, being "slowed up, or shuffling. More subtle but still uncomfortable parts of this syndrome can cause decreased social spontaneity, diminished conversation, apathy and disinclination to initiate normal activity. Akinesia and akathisia are partially treatable with anticholinergic medication, but are often treatment resistant and can be a major clinical problem.
19. Tardive Dyskinesia: (TD) This appears late, usually after years of medication use, and seems to be related to total life time dose of medication, and once it appears in full blown syndrome, it can be pernanent. (Some evidence suggests clozapine might reverse TD. -ed.) It is estimated to effect 15-20% of consumers chronically using antipsychotic meds and appears more frequent in women, in older consumers, and in those having a diagnosis other than schizphrenia. It can be prevented by early recognition and discontinuation of the antipsychotic medication if this is clinically possible. Some studies have suggested that abnormally frequent eye blinking may be an early precursor sign of tardive dyskinesia in some consumers. In other consumers, the first sign is a writhing motion of the tongue. This can progress with continued medication use to a disfiguring rhythmic distortion of the mouth or face. Other parts of the body can also be involved.
Some consumers who get very mild tardive dyskinesia find that it never gets any worse even if they stay on antipsychotic medications. In other consumers it can progress fairly rapidly over a period of months to become a very disfiguring and incapacitating movement disorder. It is impossible to predict who is at risk for progression to the severe form, and who is not. As more consumers are being treated with antipsychotic agents for a longer period of time, TD is likely to be an increasing problem. While most of the other extrapyramidal side effects can usually be controlled with Cogentin or other anticholinergic drugs, in general these anticholinergic drugs make tardive dyskinesia worse rather than better. As with other extrapyramidal side effects, increased anxiety makes the symptoms worse, and they typically disappear with sleep. Similarly, caffeine often makes symptoms worse although this varies from one consumer to another.
Antipsychotics in pregnant women
20. Use in Pregnancy: It is never possible to prove that any medication is absolutely safe in pregnancy. These drugs do cross the placenta, but there is no evidence that antipsychotic medications increase the risk of birth defects. While all pregnant women should as a general rule take as few medications as possible, pregnancy is not an absolute reason to avoid antipsychotic drug use. The stress of psychosis is also potentially damaging to the fetus, and the various risks must be weighed against each other. These drugs are also found in breast milk, and again while there is no absolute contraindication, it is probably safer for mothers taking these medications not to breast feed their babies. (Many people also suggest that if pregnant, you only use older medicines with a longer track record and avoid newer ones-ed.)
Here's an idea of how much medicine to take:
1. Chlorpromazine (Thorazine) A typical dose range for psychotic consumers is from 400-1500 mg/day in divided doses. It is commonly said that 400 mg/day is a minimal antipsychotic dose for schizophrenic consumers, although there is now increasing interest in studying the effectiveness of very low doses. Typical prn (as needed) orders for agitated psychotic consumers will be from 100 mg. P.O. or 50 mg. IM.
This is the most sedating of the antipsychotic meds, which means it is good for some agitated consumers but will also have the most sedating side effects. Because it causes consumers to feel "drugged," or "zombie like", I rarely prescribe it for use during the day but it is useful to some consumers before sleep.
1. Chlorpromazine (Thorazine) occasionally causes extreme sensitivity to sunlight and can cause opacities in the lens (cataracts) of the eye. The most sedating antipsychotics such as Thorazine and Mellaril also have the most anticholinergic side effects, including dry mouth, blurred vision, constipation and occasionally urinary retention. These also have the highest frequency of orthostatic hypotension (an abrupt drop in blood pressure when the consumer stands up).
At the same time, these drugs (chlorpromazine and thioridazine) have much less of a tendency to cause extrapyramidal (muscle) effects and there is less need to use antiparkinsonian drugs to control these side effects.
2. Thioridazine (Mellaril) - Dose is roughly equivalent to chlorpromazine (thorazine) except that it should not be used above 800 mg/day and only rarely above 400 mg/day because of the danger of irreversible changes in the retina of the eye, causing blindness. Some experts suggest that it should be used with caution in combination with antidepressants (although this is a frequently used combination) because of the danger of heart arrhythmias and sudden death.
Thioridazine (Mellaril) is a sedating drug that seems to be tolerated better than chlorpromazine with less of that drug's depressant side effects. It does not come in an injectable form and cannot be used in large doses, but for a well controlled consumer or as a night time medication it is commonly used.
Some research suggests Mellaril may have less of a tendency to cause tardive dyskinesia than the other antipsychotic meds. This is currently a controversial subject. The possibility that this may be true has encouraged some physicians to prescribe Mellaril in situations where its restricted dose range and tendency to cause sedation is not a problem.
This drug (as well as the other antipsychotics) is also useful in agitated or psychotic depression (200-400 mg/day) and in organic brain syndrome (low doses, i.e., 25 mg h.s. [before sleep] or BID [twice a day].
3. Fluphenazine (Prolixin) - Dose range 2-60 mg/day. This drug is roughly 50 times as potent as chlorpromazine and is a high potency, low dosage "least sedating" phenothiazine. It can be given by mouth (PO) or by short acting injection (IM) Prolixin hydrochloride , and also comes in a long acting esterified injectable form that lasts for over 2 weeks called Prolixin Deconoate.
4. Haloperidol (Haldol) - Dosage 1-100 mg/day. Haloperidol is a very high potency antipsychotic, and like Prolixin it is roughly 50 times as potent as chlorpromazine, so that 20 mg/day of haloperidol is roughly equivalent to 1000 mg chlorpromazine. It also now comes in a long acting injection called Haldol Deconoate. (Injectible meds are often good for consumers who have difficulty or don't want to take pills several times a day-ed.)
5. Thiothixene (Navane) - Dose 5-60 mg/day. Roughly 40 times as potent as chlorpromazine. It is only moderately sedating and is advertised as being well tolerated by the consumer and having few side effects.
6. Molindone (Moban). Dose 20-225 mg/day. A new drug, it is reported not to cause weight gain as do all of the other antipsychotics. Like Mellaril, there is some very speculative research that suggests that molindone may have less of a tendency to cause tardive dyskinesia than some of the other medications. Commonly used as a backup in consumers that have not responded well to the other, more familiar meds.
The high potency antipsychotic medications (such as Prolixin, Haldol and Navane) have a number of advantages over low potency medications such as Thorazine. The high potency drugs are relatively less sedating, cause less of the anticholinergic side effects seen with chlorpromazine, and cause less postural hypotension (drop in blood pressure from sitting up or standing up suddenly). They are also somewhat safer. However, they more commonly cause extrapyramidal side effects and are frequently used along with an antiparkinsonian anticholinergic drug (e.g., Cogentin). 20 mg/day of Prolixin is roughly equivalent to 1000 mg of Thorazine, but the Prolixin will probably be both safer and better tolerated by most consumers. This is especially true in paranoid consumers where the more sedating drugs sometimes makes consumers feel they are losing control, thereby further frightening them.
Finally, when a drug is needed in an emergency, 5-10 mg IM(Intra-muscular) of Haldol or Prolixin hydrochloride is safe and has much more antipsychotic effect than 50-75 mg. of IM chlorpromazine which is the largest safe IM dose of that drug. If additional sedation is needed, a benzodiazepine such as lorazepam can be given along with an antipsychotic medication.
Approximate oral dose of major tranquilizers
required to achieve equal potency:
chlorpromazine (Thorazine) 100 mg
fluphenazine (Prolixin) 2 mg
haloperidol (Haldol) 2 mg
molindone (Moban) 10 mg
loxapine (Loxitane) 10 mg
mesoridazine (Serentil) 50 mg
perphenazine (Trilifon) 10 mg
prochloperazine (Compazine) 15 mg
thioridazine (Mellaril) 100 mg
thiothixene (Navane) 2.5 mg
trifluoperazine (Stelazine) 5 mg
clozapine (Clozaril) 50 mg
Long Acting Injections of Antipsychotic Medications
Both fluphenazine (Prolixin) and haloperidol (Haldol) are now available in the U.S. in a long acting injectable preparation. The long acting injectable preparations are particularly useful in those consumers who might not take their drugs when they leave the hospital, or where the oral drugs do not seem to be absorbed. In addition, some consumers prefer an injection every two or four weeks to having to take a daily pill. (In addition, it puts the tension over taking meds between the doctor and consumer instead of between the consumer and his/her family. -ed). A consumer who might require the Prolixin or Haldol Decanoate injections after discharge should probably be started on the short acting form of the same drugs as soon as possible so that side effects can be assessed.
Dose equivalency between oral medication and long acting injection is highly variable from consumer to consumer. As a very rough rule of thumb l0 mg. of oral Prolixin per day is equivalent to a 12.5 mg. (l/2 cc) injection of Prolixin Deconoate every 2 weeks. 10 mg of oral Haldol is roughly equivalent to a 200 mg. injection of Haldol Deconoate every 4 weeks. There is some difference in the pharmacokinetic properties (the way they are absorbed and then metabolized, or speed of onset and how long they stay around) of the two meds. With Prolixin Decanoate the consumer tends to get an effective level of medication within a day or two while with Haldol decanoate there is a gradual, smoother uptake of medication and it may take several weeks or more to get an effective serum level. Prolixin has the advantage of working faster after a single injection, but has the disadvantage of being more likely to cause an increase in side effects for a few days after each injection. Haldol seems to stay around longer than the Prolixin. For most people, half of the medication is out of the system around 15-20 days after the injection with Haldol, and 8-10 days with Prolixin.
Clozapine (Clozaril) is a new "atypical" antipsychotic medication that has recently been released for general use. It is the first antipsychotic medication that seems to have a different mechanism of action from all of the others. It seems to cause far fewer and far less severe extrapyramidal (muscle) side effects, and it does not seem to cause tardive dyskinesia. There is even a suggestion that it might make already existing tardive dyskinesia better. In addition, clozapine seems to be effective in around 30% of psychotic consumers who have not responded to the other antipsychotic medications. So if other antipsychotics have been tried and don't work, a trial with clozapine may be warranted.
All meds have side effects, and clozapine is no exception. It is a very sedating medication, has strong anticholinergic side effects (dry mouth, blurred vision, constipation), and causes orthostatic hypotension. Other side effects include fever, headache, nausea or increased salivation. In addition, it can cause significant weight gain in some consumers. These can be uncomfortable but are usually not dangerous. Especially in higher doses, clozapine seems to cause seizures much more frequently than the other antipsychotic medications. MOST SERIOUSLY, 1-2% OF PEOPLE TAKING CLOZAPINE WILL DEVELOP AGRANULOCYTOSIS (THEY WILL STOP MAKING WHITE BLOOD CELLS). If this is discovered in time and the medication is stopped, the consumer can recover without difficulty. If this drop in white blood cells is not discovered, the person can die from infections that they can no longer fight off. There have now been six reported deaths from clozapine over the past two years, even with regular blood testing.
Everyone taking clozapine must have a blood test every week to determine their white blood count, and this must continue for as long as they take the medication. A consumer can only get medication for one week at a time, and cannot get the next week's medication without first obtaining the required blood test. Since this requirement of weekly blood tests was started, there have been no deaths from agranulocytosis, but it does mean that some consumers who might benefit from the medication do not want to put up with the hassle of the weekly tests. It also means that clozapine can only be prescribed as part of an organized monitoring system.
Finally, because of this monitoring system, clozapine is extremely expensive. The medical assistance programin a lot of states won't pay for it or places limits on who can get it. (AMI/FAMI is working to change that-ed.) This prior authorization process can take a long time. For consumers who have neither medical assistance nor insurance, the cost of the medication can preclude its use.
To decrease the risk of seizures and other side effects, clozapine is usually started at 12.5 or 25 mg/day, and then increased by 25 mg/day until a dose of 300-450 mg is reached by the end of 2-3 weeks. Subsequent increases should be no more than 100 mg at a time, with increases no more frequent than twice a week. The majority of consumers respond to 300-600 mg/day. The maximum dose is 900 mg/day, but seizures are more frequent above 600 mg. It is recommended that clozapine be taken twice a day, but in the lower end of the dose range it seems safe and effective to give it once a day if side effects are carefully monitored.
It seems to take a long time for clozapine to be effective. Some consumers who do not respond after taking clozapine for 4 weeks of at a full dose will still show a later response, and many consumers who have a partial respond have a better response as the medication is continued for six months or more.
Respiridone is the most recent of the new generation atypical antipsychotic medications to be marketed. It has few if any extrapyramidal side effects which gives it a major advantage over older medications. There is a suggestion that it may be effective in some consumers who have not responded to other medications, and may be more effective in decreasing negative symptoms. The research on these issues of increased effectiveness is not nearly as clear as the research for clozapine.
The main advantage of respiridone is its few side effects. Weight gain is a commonly reported problem, and orthostatic hypotension (sudden drops in blood pressure when the consumer stands quickly) may require that the medication be divided and given twice a day. Other side effects seem rare if the dose does not go above 6 mg/day. Potential side effects include agitation, anxiety, insomnia, sedation and nausea. Any medication can cause agranulocytosis, but the incidence of this with respiridone appears to be very low and no special blood tests or monitoring is required for safe use.
It appears from preliminary research that most consumers will respond to 6 mg/day. 2 mg/day seems ineffective, at least for most consumers, and increasing the higher than 6 mg/day cause a rapid increase in extrapyradmidal side effects with no apparent increase in effectiveness. The research literature and the package insert suggests that the medication should be given twice a day, but respiridone has a half life of around 20 hrs which means that once a day dosing should be effective. If consumers have problems with orthostatic hypotension then the dose may have to be divided.
Respiridone is an expensive medication. A standard dose of 3mgs tablets twice a day will cost over $2800 per year.
This material was created by Ronald J Diamond, M.D.
University of Wisconsin Department of Psychiatry