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Demitri Papolos, M.D. and Janice Papolos
 

Vol. 5 – Atypical Antipsychotics: Their Emerging Role in the Treatment of Early-Onset Bipolar Disorder

It's hard to believe that just about a year ago this site went live on the World Wide Web. We want to thank all of you who've visited and provided important feedback. Your responses to the July newsletter on night-terrors, in particular, indicated that many children are suffering from these parasomnias and helped us assemble invaluable data. You've enriched our knowledge base about children with early-onset bipolar disorder.

Your comments on the site also allow us to note emerging trends in prescribing practices. One of the most recent we've spotted is the treatment of bipolar disorder in children and adolescents without mood stabilizers, but rather with one of the newer, "atypical" antipsychotic drugs such as olanzapine (Zyprexa), quetiapine (Seroquel), or risperidone (Risperdal), often as a stand-alone therapy. In other words, the only medication prescribed is one of these three newer antipsychotic drugs, whose properties include antimanic effects, and so-far, unproved mood-stabilization.

Is this wise? Is this effective? Are the risks involved less than those of the mood stabilizers (lithium and several anticonvulsants)? What are the possible long-term effects? Why is this apparent shift in prescribing practice appearing now?

We spent some time reviewing the literature and interviewing some outstanding researchers and clinicians in the field because there's a lot to examine here. First, however, we need to consider the antipsychotic drugs in general, and their traditional role in psychiatry and in the treatment of bipolar disorder.

Some History

The original antipsychotic drugs were phenothiazines, originally used for their sedating and putative stress-limiting effects before general anesthesia for surgery. Parisian military surgeon Henri Laborit noticed that patients who were given chlorpromazine became remarkably calm, but remained awake. These impressions soon spread to other physicians, including the psychiatrist, Pierre Deniker. By 1952, Dr. Deniker and Dr. Jean Delay completed their first clinical trials with chlorpromazine (Thorazine and others), finding first that it was very effective in mania, and later that it diminished delusional thoughts and hallucinations in schizophrenia. Before long it was being used all over the world as a treatment for psychotic illness and, often, also for mania.

Other commonly-prescribed standard antipsychotic drugs include other phenothiazines, such as fluphenazine (Prolixin), perphenazine (Trilafon), thioridazine (Mellaril), and trifluoperazine (Stelazine), and other types of chemical agents, such as haloperidol (Haldol), pimozide (Orap), and molindone (Moban). While they all have side effects, doctors and patients and family members are concerned about the side effects that involve movement or posture--the so-called extrapyramidal side effects (EPS) that encourage use of the older term "neuroleptic" for these agents. These include early and later muscle contractions (dystonia), slowed movements (akinesia, or parkinsonism), restlessness with severe anxiety (akathisia), and later-emerging tardive dyskinesia (TD). Let us explain these briefly.

Dystonic reactions are involuntary muscle contractions that cause bizarre and uncontrolled movements of the face, neck, tongue, and back and an uncontrolled rolling of the eyes, sometimes with life-threatening compromise of the muscles required for breathing. It is quickly counteracted by antihistamines including diphenhydramine (Benadryl) or anticholinergic-antiparkinson drugs such as benztropine (Cogentin) or trihexyphenidyl (Artane).

Akinesia, or drug-induced parkinsonism, resembles Parkinson's disease, with variable tremor and slowed movements characterized by stiffness and diminished spontaneity of gestures, physical movement and speech. It is also counteracted by the anticholinergic-antiparkinsonism drugs.

Akathisia is a feeling of restlessness and an inability to sit still, as well as a subjective sensation of discomfort usually described as anxiety and often mistaken for agitation due to primary psychiatric illness, rather than a drug side effect. This very common condition is often overlooked or misunderstood, and can be difficult to treat. Sometimes, the use of the antihypertension beta-blocker propranolol (Inderal) or a benzodiazepine sedative may help.

These movement disorders are usually dealt with by lowering the dose of the antipsychotic medication, adding an antiparkinson drug, or switching to another class of antipsychotics. Generally, the more potent (fewer mg/day doses), older antipsychotic drugs are more likely to induce such reactions, whereas the less potent agents more commonly produce excessive sedation and low blood pressure. Antipsychotic agents including clozapine and the newer atypical agents reviewed here, are less likely to have such effects. Indeed, that is the main reason t hey are considered "atypical" antipsychotics.

Tardive Dyskinesia

Perhaps the most publicized side-effect of antipsychotic drugs is tardive dyskinesia, the "late appearing" disorder characterized by abnormal movements. It can present with involuntary facial grimacing, lip-smacking, chewing and sucking movements, cheek puffing, and worm-like movements of the tongue, as well as quick movements of the fingers, toes, arms and legs, or dystonic, writhing postures. Tardive dyskinesia tends to wax and wane spontaneously, and in young patients, often remits spontaneously, particularly if the offending agent is stopped.

Before the approved use of lithium for manic-depressive illness (US, 1970), antipsychotic drugs were the only medications that could control acute mania, and they were also widely employed to suppress re-emerging manic symptoms, and had value for at least the psychotic symptoms sometimes associated with depressed phases of bipolar disorder. Even after lithium and the anticonvulsant antimanic agents became available, standard antipsychotics continued to be widely used in the management of bipolar disorder patients. Nearly all adult patients with bipolar disorder have had some exposure to a traditional antipsychotic agent at some time. This usage is of particular concern due to evidence that persons with mood disorder may be at even greater risk for tardive dyskinesia than patients with schizophrenia or other chronic psychotic disorders.

The Newer "Atypical" Antipsychotics

In 1990, a new kind of antipsychotic--clozapine (Clozaril)--came onto the US clinical market. This old drug had been known since the 1960s, but was in and out of favor due to its strong association with potentially lethal suppression of the production of white blood cells by the bone marrow (agranulocytosis). However, demonstration of its superior effectiveness over standard antipsychotic drugs led to its late acceptance in the United States. Clozapine remains unique in its demonstrated clinical superiority, as well as its atypical lack of risk of EPS. It strongly stimulated development of other drugs with some similar properties, but greater safety. Among its applications include use for the management of patients with otherwise intractable forms of schizoaffective and even bipolar disorder, though formal research supporting this use remains sparse.

The first of this new generation of atypical antipsychotic agents was risperidone (Risperdal). It was followed more recently by olanzapine (Zyprexa), and quetiapine (Seroquel), and still others, notably ziprasidone (Zeldox), remain in advanced stages of clinical development. These newer antipsychotic medicines are considered "atypical" because they have relatively lower risks of acute EPS and TD, though not as low as with clozapine. They also share with clozapine interactions with a wider range of chemical messenger systems in the brain. They are not yet proved to be superior clinically. However, studies to test this hopeful prediction are ongoing.

Because the risk of TD and other movement disorders is less with these newer medicines, they are commonly prescribed in conjunction with a mood stabilizer such as lithium, carbamazepine (Tegretol) or divalproex (Depakote), sometimes with both classes of drugs used on a long-term basis. Nevertheless, it is important to emphasize that this practice remains entirely empirical and clinical, and has not yet been tested in appropriate research studies.

Clinical experience with childhood bipolar disorder patients suggests that the atypical antipsychotic agents may accomplish things and target symptoms that mood stabilizers don't. The atypicals may benefit children who have prolonged rage attacks, psychotic symptoms, mixed-irritable moods, and possibly very rapid cycling of mood--all of which are relatively commonly associated with early-onset bipolar disorder and may require different forms of treatment than are usual in adults.

"In many ways," says Mark Sandrolini, M.D., Medical Chief of Outpatient Child Psychiatry at Rush-Presbyterian St. Luke's Medical Center in Chicago, " the use of the term 'antipsychotic' is a misnomer. These drugs not only work against psychosis and mania, but they reduce hostility, and rage as well as anxiety and agitation."

The popularity of the newer atypical antipsychotics for childhood bipolar disorder patients is growing rapidly, and we have now heard of a number of cases where these drugs are prescribed alone, as the major, or only treatment offered. Usually, this practice involves drugs other than clozapine, since its potentially severe toxic effects and need for regular blood sampling to monitor white blood cell counts make it clinically less appealing than the simpler alternatives--Seroquel, Risperdal and Zyprexa. If studies of combinations of atypical antipsychotics with antimanic-mood stabilizing agents are limited, those involving monotherapy with an antipsychotic agent in children are practically nonexistent.

One mother whose son's treatment strategy called for Zyprexa as a monotherapy for his newly-diagnosed bipolar disorder wrote us and asked: "Is my child being used as a guinea pig?"

Some thoughtful and experienced clinicians are using this approach, and find that it can be quite helpful for some young bipolar patients with bipoalr disorder. For example, this past May, Dr. Raymond Behr, a highly respected clinical child psychiatrist at Albert Einstein College of Medicine and the founder of the Child Psychopharmacology ListServ for child psychiatrists, wrote about his success prescribing the atypical antipsychotics in certain circumstances as a monotherapy. He also cited two recent, placebo-controlled studies done by Dr. Mauricio Tohen and his team at Eli Lilly Laboratories, showing that olanzapine (Zyprexa) proved superior to placebo in the short-term treatment of adults with acute manic or mixed states. Similar work supports the antimanic actions of risperidone (Risperdal) as well.

We called Dr. Tohen to find out more detail. When we asked him what he meant when he stated that Zyprexa was "mood stabilizing," he told us that their studies revealed that Zyprexa not only worked on the manic and psychotic symptoms, but was also effective on the depressive symptoms of mixed states or the depressive aspects of acute mania. That statement may be a bit bewildering, but manic states are not just a constant high with grandiose and activated thought, speech and behavior. Often in adults, and very commonly in children, mania is interlaced with a rapidly shifting mood (mood lability), irritability, sadness, sleeplessness, anxiety and agitation. Dr. Tohen hastened to add that his study did not demonstrate a therapeutic effect in acute depression, nor a long-term mood-stabilizing effect on all phases of manic-depressive illness, though he indicated that such studies are being mounted.

In 1995, Drs. Gianni Faedda and Ross Baldessarini and their colleagues published an important review, entitled "Pediatric-onset bipolar disorder: A neglected clinical and public health problem." In it, they made a strong point that juvenile mania often includes psychotic features and a good deal of agitation, aggression, possibly more so than in adolescent or adult forms of the illness. They also emphasized evidence of the tendency toward an admixture of manic and depressive-dysphoric-irritable elements in kids--more than in adults--and a common lack of a clean episodic course, or very rapid fluctuations of mood and behavior in bipolar kids.

Since agitation is a principal component of mixed manic-depressive states, and the majority of children with bipolar disorder have very rapid cycling as well as commonly mixed states, it should come as no surprise that the atypical antipsychotic medications may prove to have a special place in the treatment of pediatric bipolar disorder. Risperdal, Zyprexa, and Seroquel can calm the agitation, anxiety, and rage and hostility, as well as diminish psychotic symptoms such as hallucinations and delusions.

When we contacted Joseph Biederman, M.D. at Harvard, an authority on pediatric bipolar disorder. He said: "It is my opinion that the atypical antipsychotics are much more effective in the treatment of pediatric mania than the mood stabilizers." (It should be noted that Dr. Biederman sees pediatric mania as a chronically irritable state.)

So, there is some rhyme and reason here, based on the nature of juvenile bipolar illness. In addition, the atypical antipsychotic drugs are user-friendly to children and clinicians. They are easy to administer, and, unlike the anticonvulsants, lithium, and clozapine, blood drawing is rarely required to monitor blood concentrations and regular laboratory testing is not required. Moreover, compliance with treatment is often a major issue for children. Multiple pills are hard for young children to swallow, and teenagers have a host of issues about taking any medicine. Any simplification that can be gained by a monotherapy would be welcome.

But--ease aside--do these treatments do the job and are there any negatives associated with them?

Some Negatives

As with lithium and with some anticonvulsants, two words come to mind when discussing the down-side of atypical antipsychotics: Weight gain. Not every child gains weight on these medicines, but many do, particularly with Zyprexa. And when they do, it can be astonishing. The mother who e-mailed us above about Zyprexa wrote: "He has put on eight pounds since Friday and it's continuing." Since we received her e-mail on Tuesday, we wrote back to make sure we were talking about a four-day period. "Yes," she shot back through cyberspace. That's two pounds a day, and climbing.

The atypical antipsychotics cause more weight gain than most of the conventional antipsychotic medications. Dr. Tohen told us that the weight-gain seems to be greater in children than in adults and that the younger the age the higher the risk, but that it is unclear why. In adults, there is some evidence that the weight-gain may not persist indefinitely, and may diminish after a year. Since the weight-gain usually appears right away in children, as it did in the little boy mentioned above, one can assume it will continue and consider alternative treatments. It is unknown why people gain weight (and so much of it) but it is hypothesized that the drugs' effects on the part of the hypothalamus that regulate satiety may be the root cause. Some clinicians will even mix olanzapine with risperidone and particularly with quetiapine, in order to limit weight-gain, and there are promising observations of a weight-limiting effect of the novel anticonvulsant topiramate (Topamax).

Side Effects Beyond Weight Gain

While movement disorders (EPS and TD) are less likely with the atypical than the older, standard neuroleptic-antipsychotics, they do occur. Nevertheless, the specific risks of EPS and TD with the newer drugs remain to be sorted out for children and adolescents. They appear to be very low with both clozapine and quetiapine, and are substantially higher with both olanzapine and risperidone, especially with higher doses of both drugs. Risperidone has a broad dosing range, but is often useful, and safer, at remarkably low doses, particularly in children. Risperidone and olanzapine might, therefore, be considered "quantitatively atypical" drugs since their EPS risks are not negligible, and are clearly greater than with clozapine.

Some clinicians recommend that parents of children taking any antipsychotic medicine have a filled prescription of an antiparkinson agent (such as Artane or Cogentin, or liquid Benadryl) in the house to administer immediately. Movement disorders can be terribly distressing and uncomfortable for a child and some of the movement disorders (particularly acute dystonic reactions) can be reversed quickly (within a half hour). Some physicians prescribe these drugs on a daily basis to prevent dystonic reactions from occurring. Their benefit in preventing or treatment akathisia--the sense of inner restlessness-- however, is much less convincing.

Other side effects reported are sedation, nausea, constipation, blurring of vision, nasal congestion, and dry mouth. We've heard parents complain of drooling and urinary incontinence from risperidone (these symptoms are well-known to occur with clozapine). Also, there is some anecdotal evidence and a few case reports in adults that rsiperidone and olanzapine have been associated with the induction of manic or mixed states. This may be because the atypical antipsychotics have an anti-serotonin (5-HT2) receptor blocking effect and thus are mood elevating. (We have heard of an induction of mania in children and a few adolescents, and it's something parents should be aware of.)

Finally, there are a series of general medical, metabolic problems that are being increasingly reported in association with clozapine as well as the newer antipsychotics. These include new-onset, type II (non-insulin dependent) diabetes mellitus, changes in lipid metabolism and blood concentrations, sometimes severe and persistent elevations of prolactin and other hormonal imbalances, and a range of adverse cardiovascular effects that include low blood pressure and abnormal functioning of the heart. The long-term implications of such adverse effects are not known, particularly for youngsters who may need to remain on such medication for decades to come. Moreover, we are just starting to be concerned about the potential individual and public health implications of such effects, which threaten to be at least as problematic as TD and EPS of the older drugs.

Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome is now a rare, but life-threatening, adverse reaction to antipsychotic drugs that is poorly understood. Most cases have been associated with use of relatively high, or injected doses of the more potent older neuroleptic-antipsychotic agents. The relative risks with the newer antipsychotic agents is not known, but a few cases have been reported, particularly with risperidone, the atypical most nearly like the older antipsychotics. The condition has been encountered in children and adolescents, though it is more common among the elderly. They become severely rigid and tremulous, can be very confused, and may have a high fever, unstable heart rate and blood pressure, labored breathing, and a blood test for an enzyme that is specifically released from over-stressed muscle tissue (creatine kinase) may increase dramatically.

This syndrome constitutes a true medical emergency. All antipsychotic medicines should be stopped immediately at home, and the child taken immediately to a hospital emergency service. There, cardiac monitoring, fever control, and fluid maintenance are usually administered, and drugs with muscle-relaxing (especially dantrolene [Dantrium]) or dopamine-stimulating effects (e.g., bromocriptine [Parlodel]) may be helpful. However, the primary means of limiting fatalities from this potentially lethal form of catatonia and fever is expert general supportive care.

Many people might ask: Who would expose a child to something like this or tardive dyskinesia or the movement disorders? Well, it all goes back to risk/benefit. The chances are that the movement disorders and tardive dyskinesia or NMS may not appear, but certainly psychosis, severe rage, profound anxiety, and mania are malignant for a child. Untreated psychotic symptoms or mania gravely imperils a child.

Seroquel

When we handed in the manuscript for our new book, The Bipolar Child, few doctors had experience with Seroquel and in animal testing there was some association with cataracts and high-dose Seroquel treatment in dogs. This problem was not found in monkey studies or human trials, however, and while it's a good idea to have baseline and follow-up eye examinations, cataracts do not now seem to be a major concern.

Since weight-gain is such a confounding problem--particularly in children--the risks of medical complications beyond movement disorders with most of the atypicals, may supersede the benefits of some of these drugs, particularly when clinicians entertain the idea of their use as a long-term monotherapy. For this reason, Seroquel may prove to be particularly useful, since it appears to produces far less weight gain at lower dosage ranges (50-150 mg ) than its cousins olanzapine and clozapine, and possibly less than risperidone. It may even limit weight-gain when combined with small doses of the other atypical antipsychotics.

When All is Said and Done

So, will the atypical antipsychotics replace mood stabilizers as a first-line of treatment in children with bipolar disorder? Not in our opinion, and not in the opinion of most everyone to whom we spoke. It has yet to be proved that the atypical antipsychotics actually stabilize mood over prolonged times, and prevent further episodes of bipolar depression and mixed states as well as mania, and that they do so at least as well as lithium and perhaps some anticonvulsants. In fact, lithium is unmatched in research support for long-term clinical effectiveness against all phases of manic-depressive illness and there is substantial evidence that lithium has a strong and possibly unique effect against suicidal behavior. Lithium also has been shown to prevent neuronal cell death and enhance neuronal growth, though the clinical implications of these intriguing effects are not known.

It is clear that most antipsychotic medications work very rapidly in acute mania. This advantage appears to include the newer atypical antipsychotics, although they are limited in not being available in injectable forms, and by their sometimes limited tolerability when administrated in initially high doses. Their effects on rage and anxiety are impressive. A new atypical antipsychotic is ziprasidone (Zeldox). It is likely to enter the US clinical market soon, and it does not cause as much weight-gain as olanzapine (Zyprexa).

Other potentially serious long-term risks of the newer atypical antipsychotic drugs remain to be adequately evaluated. In addition to sometimes massive weight-gain, these appear to include adverse metabolic, hormonal, and cardiovascular effects. Even the risks of EPS and TD with the newer drugs remain to be sorted out for children and adolescents.

In general, children tend to break down and eliminate most drugs more rapidly and efficiently than adults and elderly persons. That tends to protect them from drug side effects. However, there is both laboratory and clinical evidence that children and younger animals are more sensitive to antipsychotic drugs than adults, and require much smaller doses. As the optimal dosing with the newer antipsychotic drugs is worked out, it is wise to start with low doses in children. For example, daily doses of Risperdal of 0.25 to 2.5 mg, 2.5-5 mg of Zyprexa, and less than 200 mg of Seroquel may suffice. Hopefully, such doses may also limit side-effect risks.

Gianni Faedda, M.D. of the Lucio Bini Center for mood disorders research in New York City wrote us the following statement when we spoke to him about this newsletter. It seems appropriate to end this discussion with his words:

"In children and adolescents, Risperdal, Zyprexa, and Seroquel are useful in the acute and maintenance treatment of bipolar disorder. Although I have used both Seroquel and Zyprexa in monotherapy in selected cases, I am not willing to advocate their routine use as monotherapy, as the available data remain inadequate to justify this practice."

I remain of the opinion that all the effective mood stabilizers are antimanic agents (with the possible exception of lamottrigine (Lamictal). Their mechanism of action is probably not unitary, and some patients respond to one but not to the other.

Until their safety and efficacy both in the acute and maintenance phases of treatment are proven, they should be used as second-line agents or as add-ons, unless there are compelling reasons (such as failure to respond to a combination of lithium and an anticonvulsant, or inability to tolerate therapeutic doses of the mood stabilizers)."

Dr. Faedda went on to say something else very important: "It should be emphasized that antidepressants can cause a trial of a mood stabilizer to look as though it has failed because the antidepressants can be very destabilizing for a child or adult with bipolar disorder. Stimulants can do the same thing. Therefore, a gradual tapering of antidepressants and stimulants and an assessment of response to mood-stabilizing agents should precede the addition of antipsychotics--typical or atypical."

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We'll write again soon. Meantime, let us know how your children are responding to any of the medications mentioned above. We'll keep asking the questions and monitoring the research findings as they appear and report back what we find.

We send you our best,

Janice Papolos and Demitri Papolos, M.D.

The authors wish to thank Ross J. Baldessarini, M.D., one of the foremost authorities on antipsychotic medications, for his invaluable contribution to this newsletter.

References

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Baldessarini RJ: Personal written correspondence, September 12 and 25, 2000.

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Demitri Papolos, M.D.

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