Friday, December 5, 2008

Antipsychotic Medications

Antipsychotic medications are frequently prescribed by psychiatrists. They help directly to reduce symptoms such as hallucinations, extremely disorganized thinking, suspiciousness, agitation, or delusions.

The first conventional antipsychotic medication was chlorpromazine, which began to be studied in the treatment of schizophrenia in the early 1950's. Many other antipsychotics were developed afterwards.

There is not much evidence that any one of the conventional, or "typical" antipsychotics works better than another. But there are differences in side-effects: some of these drugs--such as chlorpromazine-- are more sedating; others are less sedating but more prone to cause muscle stiffness--such as haloperidol.

All of the older antipsychotics cause an increased risk of developing a movement disorder called tardive dyskinesia, in which there is abnormal, involuntary muscle activity, often involving the mouth or tongue. Sometimes tardive dyskinesia can be irreversible. The risk is approximately 20-30% for individuals taking older antipsychotics long-term; the risk is probably higher in women, in the elderly, and in those with mood disorders.

I have not prescribed an old "typical" antipsychotic in years. But some people may have taken them for years, and may prefer to continue with them, especially if they are benefiting from the medication without having side-effect problems. They are still used quite frequently in hospitals, since they come in an injectable form which can more rapidly help to calm some extremely agitated patients who are unable to take oral medication.

In recent years, a new class of antipsychotics has appeared on the market; these are usually called "atypical antipsychotics". These include risperidone, quetiapine, olanzapine, ziprasidone, and clozapine (there are a few other newer ones, less commonly used in Canada).

Initial enthusiasm for these new antipsychotics led to various claims about their superiority over the older drugs for treating symptoms of schizophrenia. There is a lot of marketing money being spent on the atypicals. But there is more evidence right now that they actually don't work very much better than the old drugs, if at all. However, the evidence is quite clear that the atypicals have a smaller likelihood of causing movement disorders, especially tardive dyskinesia. For this reason, I consider them to be the drugs of choice to use when prescribing antipsychotics.

Because they are safer than the older drugs, the atypicals have been used quite liberally to treat other psychiatric symptoms aside from those of schizophrenia. They are probably useful mood-stabilizers to treat or prevent manic episodes in bipolar disorder, and there is also evidence that they can be useful adjuncts to treat symptoms of depression. Many of my patients, who may have mixed symptoms of anxiety, depression, primary insomnia, and emotional lability under stress, benefit from small doses of atypical antipsychotics, at least for short periods of time.

There is not much evidence showing that any one atypical antipsychotic is superior to another, with a few exceptions:
1) olanzapine may be slightly superior to other antipsychotics except for clozapine. However it has worse side-effects, including weight gain, which can sometimes be severe.
2) clozapine is without a doubt the most effective antipsychotic. For the majority, it works about as well as any of the others. But for a significant minority (maybe 30% of people) it is markedly superior, and leads to a vast, sometimes miraculous, improvement in symptoms and quality of life. However, clozapine has serious side-effect problems, including a small life-threatening risk that white blood cell levels can drop dangerously (agranulocytosis). Also there is a small but significant risk of seizures. So, at this point, the standard practice is to reserve clozapine for those who have attempted several other antipsychotic medications without adequate benefit.

Antipsychotic medications are imperfect. For the majority of people, they are helpful in reducing psychotic symptoms, and are tolerated reasonably well. For some, they almost instantly and completely relieve symptoms. For many others, they do not reduce symptoms very well, and may merely cause a type of unwelcome sedation. The sedation can feel like sleepiness, but often the most bothersome type of sedation from antipsychotics is a feeling of indifference, or emotional restrictedness. A common phenomenon among people struggling with schizophrenia or bipolar disorder is of stopping medications against medical advice -- often people stop the medications because they don't like the side-effects, and they don't feel feel that the medication is helping with respect to quality of life.

In any case, it is certainly true that it can take time for antipsychotics to work best. There is some evidence that a full therapeutic effect may accumulate over a period of at least 6 months. So I encourage people who are giving these drugs a try to be patient with them, to give them a chance. Also, there are a variety of options to choose from, and sometimes one drug can suit a person better than another. Dosing is another matter; sometimes larger doses deserve a thorough try; other times it can be worth trying a much smaller dose, which may work as well, with fewer side-effects, provided it can be stuck to consistently for a long trial (e.g. at least 6 months).

--a study summarizing the expected effects of a standard antipsychotic (in this case, chlorpromazine) in schizophrenia; in general, the evidence supports that relapse rates are reduced by at least 50%, with a modest improvement in quality of life and symptom control--
--an important study showing no advantage to quality of life among those using atypical antipsychotics, compared to those using older, typical antipsychotics, in fact the data from this study show a slight advantage for the older drugs--
--a summary of an important study showing a slight advantage of olanzapine over several other atypicals, and with the older typical antipsychotic perphanazine working as well as these other atypicals--
--a study showing no significant difference in effectiveness between risperidone and olanzapine--

--another large recent meta-analysis showing a slight advantage for olanzapine and clozapine--

--another major European study showing a slight advantage for olanzapine and clozapine over other antipsychotics--
--a study showing that extremely high doses of olanzapine (over 30 mg/day) may work as well as clozapine for treatment-resistant patients with schizophrenia; but the olanzapine caused more weight gain--
--a very recent study showing that clozapine is markedly superior to high-dose olanzapine for treatment-resistant adolescents--
--a study showing a reduced rate of tardive dyskinesia in patients taking atypical antipsychotics, compared to those taking typical antipsychotics. Of note, this study showed a risk of tardive dyskinesia in patients not taking any antipsychotic at all, and this rate was actually slightly higher than the rate in patients taking atypicals. This is consistent with some evidence that atypicals such as olanzapine and clozapine may actually be used to treat tardive dyskinesia--

--a nice long-term study showing that antipsychotic+mood stabilizer (in this case, fairly low-dose quetiapine plus either lithium or valproate) was much superior to antipsychotic alone or mood stabilizer alone in preventing relapses in bipolar disorder--
--a study showing that an atypical antipsychotic (in this case, risperidone) can reduce suicidal ideation and other symptoms when added to an antidepressant in treating depression--

It should be noted that the results of these studies, as with those from most studies, give us ideas about how groups of people with specific diagnoses respond to certain treatments. The studies rarely tell us how a particular individual would respond to a given therapy; I find that in clinical practice, sometimes one particular medication or therapy suits an individual much better than another, regardless of what the studies show. In this case I think the studies show that a whole variety of different medications--including the older ones--have a decent chance of working, and so I think this could instill some hope that it can be worthwhile for an individual to keep searching for the one that works best.


Anonymous said...

With regard to atypical antipsychotics and weight gain,
Which one, in your opinion, will cause the lease amount of gain?

I was looking at this--

But am not quite sure about it.

Also, are there any specific atypicals that are not approved for use in canada?


GK said...

Here are some more recent references:

It appears that ziprasidone has the smallest tendency among the atypicals to cause weight gain.

Risperidone is probably second-best, followed by quetiapine.

All three of these above are probably quite similar in terms of causing heightened risk for metabolic disease.

Clozapine and olanzapine probably have a significantly greater tendency to cause weight gain and metabolic disease risks than any of the others, with olanzapine probably have the largest effect of all.

In my experience, risperidone or quetiapine can be reasonable choices to minimize weight gain. I haven't had much experience prescribing ziprasidone yet; many of the newer drugs do not get covered by some of the medication plans. Also it is my impression that ziprasidone is slightly inferior in terms of effectiveness compared to the others, so it makes me think of risperidone or quetiapine first.

Aripiprazole is not yet available in Canada; it seems to be marketed quite aggressively in the U.S.

Anonymous said...

Is there a dose response relationship between Seroquel and an increase in baseline weight, blood glucose, total cholesterol, triglycerides and blood pressure?

Or- are the development of these physiological symptoms more dependent on the length of treatment?

I am finding it hard to find papers with a dose comparison. Many compare inter-drug differences.

I was looking at some medline/pub med articles and cross referenced some of the authors only to realize they are working with/funded by AstraZeneca. (Can you say COI?)


GK said...

Good question. Intuitively one would think that higher doses would pose a higher risk.

Here's a study looking at olanzapine showing a relationship with genetic factors, an inverse relationship with baseline BMI, a positive relationship with treatment duration and with clinical improvement, but no relationship with dose (HOWEVER, the doses here were all medium to high, not ultra-low):

This supports my own observations, that at full doses, titrating atypical antipsychotics up or down may not make a lot of difference with respect to metabolic side effects.

However, few studies have looked at the use of very-low-dose antipsychotics: in practice we often use Seroquel under 300 mg daily (sometimes as low as 6.25 mg) -- at these doses, I think there is probably a much lower likelihood of metabolic side effects. My guess would be that metabolic risk increases substantially as full doses are approached, then there is a relative plateau. For Seroquel, these full doses would be in the 300-600 mg range.

Here is a reference to a retrospective study showing no weight gain or lipid problems after one year of low dose atypicals in elderly patients (doses of Seroquel were about 50-100 mg/d):

Anonymous said...

Given that atypical anti psychotics (Ie seroquel) have a higher receptor affinity for 5-HT receptors than dopamine receptors, how is it possible to achieved a dopamine blockade without a histamine blockade? (and the sometimes unwanted sedation and somnolence associated with this blockade).

If it is possible: Do you know how?

My postulation was perhaps there is a receptor quantity difference in the particular area of the brain being targeted?

Or perhaps the drug binds differently or for a different duration to different receptors?

Or perhaps at one receptor it acts as a partial agonist and a complete antagonist at another receptor site?

Or perhaps the receptor turn over rate is fast for one than the other?
(ie- endocytosis of the blocked receptor and/ or subsequent up regulation of receptor translation or membrane mobilization of vesicle bound receptor storage sites?)

Just thinking...wondering...? No rush.

If you come across anything, I would be interested

I will look into it in the mean time.

Thanks =)

GK said...

Good questions. Aside from the different neurotransmitter effects each antipsychotic has, it may be that different drugs could have different profiles of regional activity. Differences in metabolism may be relevant also: it may be that continuous receptor blockade, or re-uptake blockade, is not required for a medication to work -- possibly just a few hours per day could work just as well, in terms of antipsychotic effects, since the overall symptomatic impact of the blockade may be long-term downstream effects (this is my hypothesis). Analogously, one does not have to take violin lessons 24 hours per day in order to learn the violin optimally. Perhaps 6 hours a day would do, and any more than that would just become a nuisance!

Side-effects, though, such as sedation, are very much dependent on immediate receptor blockade. Thus, some shorter acting dopamine-blockers may be able to help with symptom change without as much of a side-effect burden. (my hypothesis would need to be tested, of course).

Another important angle on this question is to consider that the multiple receptor activities of some atypicals (such as clozapine) may be required for benefit. Dopamine blockade, per se, is not the goal -- improvement in symptoms and quality of life is the goal! Clozapine is a "messy" drug in terms of its very many receptor actions; yet it is the best antipsychotic of all.

In terms of managing side-effects such as sedation, I think one could plan an approach based on some understanding of the pharmacology -- but finally the solutions are all empirical. I've listened to many a talk on biological psychiatry in which the speaker rambles about receptor affinities, etc. -- yet all this knowledge usually doesn't make much difference in terms of how to manage side-effects: usually to reduce sedation, one has to reduce the dose of the causative agent, or to add a pharmacological or behavioural treatment for sedation.

One more point: central histamine blockade may actually be a useful mechanism to potentiate restful sleep: some recent studies of low-dose doxepin suggest this. Restful sleep itself could be an important aspect of helping with many mental health conditions, including psychosis, mood disorder, anxiety, etc.