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During the acute psychosis, particularly first rate, you’re really concerned about safety, containment. Again, we talked about filtering of environmental stimulation. Try to reduce stimulation from the environment and stress and developing alliance early on in terms of psychological interventions, minimizing medication side effects which is crucial in terms of your alliance and then working with the antipsychotic.
When I see first rate patients or patients in complication early in the course I also insist having the family or the parents come with the patient. Obviously I‘ll meet with the patient first alone but then I always bring in the parents because this is an illness that impairs judgment and affects the family and family involvement is crucial. In the long term, psychosocial treatment individual treatment is important.
Assertive case management or so-called TAC treatments – community treatment programs – where making use of outreach is very important for noncompliant patients, for people who have relapsed. There is no literature on cognitive behavioral approaches in schizophrenia.
Probably the most effective intervention is actually family work. Education, working out on the expressed emotion which is the intent affective expression and criticism. Excessive enmeshment can be very helpful. It’s important not to in any way imply that this is an illness caused by the family but rather we’re helping the family through education.
There’s a new model where families meet in groups with education and then the families become support groups because families, because of the stigma, become very isolated and sometimes are just at a total loss how to handle their child with schizophrenia. Increasingly we’re finding if you bring several families together in these organized groups or mentally ill, they can really support each other, break through that isolation and be quite helpful.
Don’t worry about all this information. The outline contains a lot of information if you’re studying for an exam but I’m just going to be highlighting some of the more important points. Basically psychosocial treatment there’s no question, family treatment, family education reduces relapse rates and that’s been well established. Social skills probably to a lesser extent but social skills are valuable. There’s no question that programs for assertive community.
I think the best example is I have a patient who had been on haloperidol with treatment resistant voices, auditory hallucinations and I switched him to olanzapine and a month later he came in thanking me for the olanzapine. No one thanks you for starting them on Haldol. It just doesn’t happen but he was thanking me for olanzapine. I said, "Well, how are the voices?" He said, "Oh, they love it too." But I think that sort of captures this whole new idea that with cognitive therapies, you know, we can find that he’s now working full time. Patients can, in fact, function with residual psychotic symptoms and we really need to expand our view of target symptoms.
So general target symptoms of these drugs they are antipsychotics. The atypicals are better for negative symptoms. All of these drugs treat agitation although often agitation can be better treated with drugs like lorazepam. Then the final cluster of symptoms that we’ve had less success with are cognitive impairment and a lot of attention is now directed that way.
A little bit about how antipsychotic drugs work. We really are limited in our understanding. It’s best to think of them in terms of acting in two stages. When you first give an antipsychotic drug, all of these block dopamine D2 receptors so the postsynaptic D2 receptors are blocked. Also autoreceptors, which are D2 receptors, are blocked and when you block the autoreceptors acutely you get an increase in discharge of presynaptic neurons and increase in release of dopamine. So you’re blocking postsynaptic receptors and by blocking autoreceptors you’re increasing activity presynaptically. The conventional antipsychotics block about 70-90% of dopamine receptors. Clozapine and olanzapine probably produce therapeutic effects at much lower rates of D2 blockade, on the order of 40-60%.
Now, after a delay of about two to four weeks you start seeing several changes. You get post synaptic increase in the density of D2 receptors so an increase in D2 receptors causes dopamine hypersensitivity. Presynaptically a significant percentage, probably a half to two-thirds of presynaptic dopamine neurons, become electrically silent and that’s known as depolarization blockade. It’s thought that it’s the depolarization blockade that produces the neurologic side effects and possibly the antipsychotic effects.
The conventional antipsychotics produce depolarization blockade in both the nigra striatal pathways which results in EPS and also in the ventral tegmental dopamine neurons, mesocortical and mesolimbic dopamine neurons. The atypicals seem to spare the nigra striatal dopamine neurons and by not causing depolarization blockade in the nigra striatal dopamine neurons it’s probably how they prevent EPS. These are the different pathways. Again, all of these drugs are causing depolarization blockade and the ventral tegmental dopamine neurons extend to the cortex and to the temporal lobe structures. Atypicals preserve the nigra striatal dopamine neurons.
Side effects. With the conventionals we really do need to talk quite a bit about side effects because these can be very problematic. So those associated with the high potency agents are the EPS which we will talking about. The low potency conventionals cause a different group of side effects: sedation which sometimes is used in patient units to create that sort of zombie effect, hypotension, weight gain is a problem with all these drugs. The exception is molindone which sometimes actually can cause weight loss and then the low potency drugs tend to be anticholinergic. So if you’re using a drug like flurazepam or Mellaril, be very careful in terms of adding it to other anticholinergic agents and be very careful in the elderly.
On side effects which are related to D2 blockade independent of potency are hyperprolactinemia where we get the amenorrhea, galactorrhea and sexual dysfunction, tardive dyskinesia and neuroleptic malignant syndrome. So you can get all of these side effects with any D2 blocker. TD, as I’ll be talking about in a few minutes, is probably less of a risk with the atypicals.
Conventional agents can also produce a few hideous tardive dyskinesia side effects. They can impair heat regulation so you have to be very careful about hyper or hypothermia in patients on conventional antipsychotics. Pigmentary retinopathy you should all be aware of with high dose Mellaril. Never exceed 800 mg per day. Exposure for as short as two to four weeks has been associated with blindness with Mellaril. So that’s an absolute contraindication to high dose Mellaril.
Then the older drugs, you know, chlorpromazine and thioridazine do in fact have a literature on sudden death from cardiac effects. Be aware of high dose low potency agents affecting EKG and also pimozide which is a calcium channel blocker, you should monitor EKGs when starting pimozide.
A few drug interactions you should note. Conventional antipsychotics are mostly metabolized by 2D6 so drugs that act on 2D6 like the SSRIs which inhibit 2D6 will increase neuroleptic levels. Fortunately, most drug interaction studies find no real clinical effect in increasing the drugs. They’re very safe drugs. The only one that’s really a concern is clozapine, drug interactions that can double or triple. Clozapine can actually be quite dangerous and in our experience because clozapine is metabolized by the 3A series and 1A you have to worry about erythromycin and fluvoxamine which inhibit 3A. Potentially nefazodone as well. We’ve seen patients become very toxic when erythromycin or fluvoxamine are added to clozapine it can double or triple blood levels.
Tobacco smoking increases the 1A enzymes, can lower antipsychotic levels so don’t try to fine tune dose on a smoke free inpatient unit because the metabolism will change when the patient goes back to smoking. Anticonvulsants can lower blood levels of most drugs. It’s been shown including for haloperidol and clozapine. I would say that the two I would be most aware of are fluvoxamine and erythromycin added to clozapine which can actually be quite dangerous.
The extra pyramidal side effects. First, very important is dystonic reactions. I’m not going to go through all the points but it’s important that you just understand that dystonia is a very frightening, uncomfortable side effect – this sudden spasm of any muscle in the body – and if it affects the larynx it can actually be fatal if you get laryngeal spasm with occlusion of the airway. You want to avoid dystonia at all cost because say a first rate patient who’s reluctant to take medication two days after seeing you has this horrible experience will never again want to take medication.
Risk factors which are important tend to occur within the first four days of starting medication. Young patients are much more highly at risk than older patients. After about age 40 their risk is very low and high potency agents are much more likely to cause it than low potency agents. There is also tardive dystonia which is a variant of TD.
To prevent it, the easiest way is obviously to use an atypical antipsychotic but if you’re going to be using a conventional you should use prophylaxis typically Cogentin, benztropine bid. Because this is a side effect of the first week of treatment you can taper and stop the benztropine after one to two weeks.
Then acute treatments. Because this can be life threatening, you know, be aware that you can give these treatments PO or IM and if you have IV access you can get Benadryl IV in the case of laryngeal spasm. If you treat acute dystonia be aware that Cogentin duration of efficacy is only about six to eight hours so don’t say give the patient a single dose of IM Cogentin in the Emergency Room and send them out. Always give them, then, supplemental oral Cogentin to take for a week or so because they remain at risk.
Akathisia is an also a very serious effect. Studies have shown that as akathisia emerges patients tend to get more psychotic, much greater risk for noncompliance, for violence and for, you know, signing out AMA. It’s often misinterpreted as psychotic agitation so if you see a patient pacing who can’t sit still. Some patients only experience it as pain in their lower extremities. Usually it’s akathisia.
The risk factors. Most important is high potency agents can affect patients of any age. Often can be quite chronic. There is tardive akathisia which seems to be an irreversible form of akathisia. If the patient develops akathisia… there’s really no reason with the newer drugs for any patient to have akathisia given what a serious adverse effect it is and it can have such important clinical consequences. Intervention usually is just a switch to a newer drug.
Any of the atypicals seem to much better in terms of akathisia. It is dose related so sometimes you can get rid of it by lowering the dose. Beta blockers, interestingly, tend to be helpful for akathisia. So the one form of EPS response with the beta blockers is akathisia. But again, in most cases, we would respond to akathisia with a conventional by starting an atypical agent. The exception, of course, that someone is on depo neuroleptic then we’d probably use a beta blocker.
Parkinsonism is often mistaken for negative symptoms. It’s, you know, the mask-like facies, the psychomotor retardation. It can occur at any age but tends to be more common in young patients and in the elderly. More common with high potency agents and it’s dose related. It can also be very disabling. The same sort of responses. I would say patients who are very psychomotor retarded and it’s hard to know if it’s severe negative symptoms. They persist on risperidone and olanzapine but then when I’ve switched them to Seroquel, the psychomotor retardation completely disappears.
So sometimes it can be difficult to sort out Parkinsonism from negative symptoms but it’s dose related so you can lower the dose. You can add anticholinergic agents but be very careful in the elderly. Sometimes amantadine is safer in patients who are sensitive to anticholinergic side effects. You can see agitation and psychosis with amantadine so be careful. Then usually we will switch to an atypical if Parkinsonism is present. We don’t recommend Sinemet with our dopamine agonists.
This is a figure from an important study. It was in the elderly looking at the risk for tardive dyskinesia in patients who develop Parkinsonism early on in the first few months of treatment versus patients who did not develop EPS or Parkinsonism. So this is just to make a point that early Parkinsonism or EPS is a very powerful predictor of tardive dyskinesia so be aware of that. If someone is developing Parkinsonism it may be another reason to switch to an atypical.
Tardive dyskinesia is the dreaded late developing choreiform. By choreiform we just mean it’s quick, nonrhythmic movements. Some people have mistaken choreiform for writhing. It’s not writhing. It’s quick, non-rhythmic movements most commonly orobuccal muscles. Again, there’s the variant of tardive dyskinesia known as tardive dystonia which is the persistent dystonic posturing or persistent muscle spasm which can be very painful.
Risk factors for TD. Age is the most important risk factor. Young patients have a risk about 5% per year cumulative. The elderly can develop TD at a rate of 30% in the first year, as high as 60% in the second year of exposure. So the elderly have much higher rates. They also have high rates of spontaneous dyskinesias independent of neuroleptics.
Affective illness and increase in higher dose have been associated in some studies but not other studies. So it’s in the literature that affective illness in higher antipsychotic dose are risk factors but it’s not conclusive. But you should be aware of it. Again, Parkinsonian side effects early on. It turns out diabetes is also a pretty strong risk factor. It’s probably related to oxidative burden associated with diabetes. There’s now encouraging data, it’s not fully established but it’s encouraging enough that I think we should all be aware of it and we should even make patients and their families aware of data suggesting that the atypicals, so far risperidone and olanzapine, may in fact present substantially lower rates of TD.
This is data derived from a large olanzapine versus haloperidol studies, this showing the rate of patients not producing new TD in these studies of varying duration compared to haloperidol. Olanzapine was associated with significantly less TD in these studies looking at patients who had no TD at the start of the study. Typically with these studies it’s often a matter of showing a difference between say 5% annual rate and 1 or 2% annual rate so you really need thousands of patients to conclusively show that sort of difference. Olanzapine has shown in animal models producing these sort of chewing movements that olanzapine and clozapine produced much less in the way of chewing movements in animals compared to conventionals.
A study which may be a little more compelling with risperidone took advantage of the very high rate of TD in elderly patients. It’s easier to show a difference if the rate’s much higher. So you see 30% the first year, 60% in two years compared to trying to show the difference in a rate of 5%. So this may be a little bit hard to see but this was matched patient groups, roughly 50 elderly patients, not always schizophrenia, some with dementing illnesses, started on low dose haloperidol and low dose risperidone on the order of 0.5 to 2 mg a day. You can see patients on haloperidol had the
Treatment. There’s no good treatment for TD. You can stop the antipsychotic if they don’t need it but in most cases the patient does need it. Clozapine has been shown to decrease the severity of TD or increase the rate of remission. Some new, less rigorous studies are suggesting the atypicals also are associated with a reduction in TD when patients are switched to them. So it may make sense to switch to atypicals.
There’s a literature on vitamin E which in three or four early small studies showed improvement of TD if started within the first three to five years. A very large VA study just came out which did not find effectiveness but most of the VA patients had TD of longer duration. I would still recommend
Neuroleptic malignant syndrome. Again, very important that you all be aware of it. It can probably occur with all these drugs – conventional and atypical. I find that it is missed sometimes because in some cases it gradually evolves so it doesn’t always just occur suddenly with all the symptoms at once. When it evolves, the first sign usually is just sort of confusion or fluctuating consciousness and then the patient may look like they’ve just developed severe Parkinsonian side effects. As it goes on slowly and typically a patient starts to seem a little confused and a little stiff and sort of Parkinsonian and then they’re sweating a little but it’s summer and you’re not really that concerned. They become a little bit mute and then these last more serious life threatening side effects can then occur abruptly, within 24 hours. If the evolution has proceeded slowly sometimes this final development can be missed and that’s autonomic instability, blood pressure pulse change. Hallmark is the temperature that goes up, the patient
Olanzapine and quetiapine represent drugs which were produced by tampering with the clozapine molecule. So these two drugs attempt to alter clozapine enough to avoid agranulocytosis and so these two also act on many different neurotransmitters. Risperidone represents more of a targeted approach to primarily 5HT2 and D2 receptors and zeprazidone which is coming out soon is similar. We’re going to talk about clozapine first. Again, I’m not going to go into the details. We’ve already talked about the dopamine effects of clozapine. It acts on many other receptors as I’ve talked about and, again, I think it may end up being important that it acts on the end of the A receptor as well but because it acts on so many receptor sites we get a whole host of side effects.
Typically, 300-600 mg a day and our average patient probably gets about 500 mg a day. Half life of about 16 hours. You can give it at 2HS dosing although sometimes you need to divide the dose because of the side effects and it’s metabolized by 1A2 and 3A4. So, again, susceptible to agents that inhibit 3A4 like fluvoxamine, erythromycin. Cigarette smoking affects 1A2 and the anticonvulsants also induce both of those receptors.
Update on efficacy and you’re all aware that it’s more effective in treatment resistant patients. 30% of patients respond at six weeks. As many as 50% in six months. It seems to prevent relapse possibly independent of its antipsychotic effect. It’s a good mood stabilizer. It improves negative symptoms compared to haloperidol. It’s so far the only drug demonstrated to improve polydipsia and hypernatremia – so-called water intoxication. Very effective for reducing hostility and aggression. I think some of the most dramatic effects we’ve seen have been in aggressive, violent patients.
Some evidence now suggests that it reduces suicide rates and there’s a large international study going on and also some preliminary evidence that it reduces substance abuse and cigarette smoking. So clozapine is much more than just an antipsychotic drug. It has a whole range of efficacies.
Starting clozapine. Very important to give a test dose, a very small dose of 12.5 milligrams just to make sure the patient tolerates it, particularly looking for hypotension and then depending on whether you’re doing it in inpatient or outpatient you can go slowly or rapidly. We compare patients all the time in clozapine outpatient and it can take us one, two or even three months to complete it. But it’s the process of adding on clozapine until you usually
Risperidone was the first of the drugs following the discovery that among other effects, clozapine had a very high 5HT2/D2 ratio and risperidone really ushered in the whole serotonin-dopamine antagonist idea. It also acts on D4 receptors and noradrenergic and histaminergic receptors. The combined half life of risperidone and its active metabolite is 24 hours so you can give risperidone once daily dose which is actually very important.
It’s metabolized by 2D6. It has been said that drugs that affect 2D6 merely alter the ratio of parent compound and active metabolite. So it’s been said
Efficacy of risperidone. Compared to 20 mg a day of haloperidol, fewer EPS. More effective for negative symptoms. Again, there’s the debate about whether this represents primary negative symptoms or Parkinsonian side effects of haloperidol. But importantly in these studies, risperidone actually was more effective for psychotic symptoms. So of the newer generation of atypicals, risperidone is the only drug that has consistently shown greater antipsychotic effect compared to haloperidol.
Olanzapine, again, has a very favorable serotonin dopamine ratio. It has anticholinergic activity in vitro but there’s growing evidence that it probably isn’t clinically significant. In vivo it probably is acting more as an agonist than an antagonist. It doesn’t seem to cause cognitive deficits in the elderly. It’s metabolized like clozapine by 1A2 and 3A4 so the same drug interactions are possible although they’ve not been studied. You can give it once a day because of its long half life and it’s best to give it at bedtime.
Generally, you can start at 10 mg a day in the nonelderly. Most patients require at least 15 mg a day and anywhere between 10 and 20 mg a day is usually adequate. There is very little data on higher dose olanzapine but I have seen the occasional patient who seems to require 30 mg a day and
Quetiapine or Seroquel is a drug that we know the least about, we have the least experience with. The whole atypical story is still developing in terms of how these drugs compare so we’re really waiting to get more data from head to head trials so we know how best to use these.
But quetiapine has a very good D2 to 5HT2 ratio. It’s the only drug like clozapine that gets by with less D2 occupancy. Not anticholinergic at all but it does have alpha-adrenergic antagonist properties so it can cause substantial hypotension and you have to be quite careful with it, particularly in the elderly. It’s metabolized by 2D6 and 1A2.
Half life is short, six hours, so theoretically it requires bid dosing. Some clinicians are using it once a day and saying it seems to be working. We really don’t know if peripheral half life really does tell us much about brain levels at key receptors in the brain but until we know more it’s best to get it on at
Risperidone you can sometimes lose efficacy if you raise the dose too high so it makes sense to have a time limited trial of higher doses of risperidone up to 12, you know,16 mg a day. Again, if you see no improvement or if you start to see EPS, back off. Particularly on conventional neuroleptics it makes sense to actually reduce the dose in treatment resistance if you see EPS because the presence of EPS often is associated with worsening of psychosis.
If those two interventions have not helped then it makes sense to switch the antipsychotic drug. As I’ve said, although the atypicals on average may seem very similar, my experience is there are very often idiosyncratic responses to these drugs which I cannot predict and some patients do much
There is literature on adding lithium. Often it’s quite helpful particularly in the presence of affective symptoms but also in the absence of affective symptoms. Some patients seem to improve with lithium. ECT is sometimes helpful particularly early in the course of treatment. Some clinicians will give ECT and then, say, start clozapine immediately afterwards. Some clinicians give maintenance ETC. There’s less experience with that with not much data.
Antidepressants can be very helpful for comorbid depression and in some patients SSRIs seem to be helpful for negative symptoms. Be aware that SSRIs elevate conventional neuroleptic blood levels. There is one study performed by Kramer about 15 years ago found that adding tricyclic antidepressants in acutely psychotic patients.
I find some patients with comorbid anxiety and particularly on conventional neuroleptics patients who have sometimes EPS and tension seem to do very well with adding Buspirone so I would recommend Buspirone in patients with schizophrenia with anxiety group sense of distress.
Then also when patients continue to relapse don’t forget about all the psychosocial dimensions which I’ve talked about. It can be crucially important to
Finally, I’ll end with ziprasidone. Ziprasidone or Zeldox is Pfizer’s entry into the atypical drugs. It was not approved with the initial submission to the FDA. It may be in approval in the year 2000. It’s another atypical, not too different from risperidone in certain aspects but the advantages of it primarily are it causes