Promising Medications for Axis I Disorders

More than 80 medications are in development to treat mental illnesses, including 18 for depression, 15 for schizophrenia and 16 for anxiety disorders, according to the Pharmaceutical Researchers and Manufacturers of America (1998). Which ones will most likely come to market in the United States?

Attempting to answer that question are Ira D. Glick, M.D., and Joseph K. Belanoff, M.D., of the department of psychiatry and behavioral sciences at Stanford University School of Medicine. They presented a poster session, "New Psychotropic Drugs for Axis I Disorders: Recently Arrived, In Development and Never Arrived," at the 37th annual meeting of the American College of Neuropsychophar-macology (ACNP) held in December 1998 in Puerto Rico.

To prepare for the presentation, Glick and Belanoff, along with Jacob S. Ballon, a colleague from the University of California, Los Angeles, reviewed the controlled trials reported in the literature. They also contacted expert psychopharmacologists-clinicians in the United States and Europe, and representatives of the pharmaceutical industry.

Antipsychotics

Promising drugs in development for schizophrenia include ziprasidone (Zeldox, Pfizer, Inc.), aripiprazole (Otsuka America Pharmaceutical), M100907 (Hoechst Marion Roussel Inc.) and ORG 5222 (Organon Inc.), according to their research. A serotonin-dopamine antagonist, ziprasidone has been efficacious in blocking dopaminergic behaviors in animals. Trial data have shown the drug's effectiveness in treating both positive and negative symptoms of schizophrenia (Keck et al., 1998).

"With ziprasidone, they are waiting for more studies on the issue of the QT interval, although it doesn't look like it's a clinically significant problem," Glick said in a recent interview with Psychiatric Times.

Early studies with aripiprazole, an antagonist at postsynaptic D_2A receptors, and an agonist at presynaptic dopamine autoreceptors, show reduction in psychotic symptoms with a favorable extrapyramidal side effect (EPS) profile, according to the presenters. Animal models indicate the drug has less potential to cause side effects because of the relative lack of upregulation of D₂ receptors in the striatum (Inoue et al., 1997).

M100907 (formerly MDL 100907) is a selective 5-HT_2A antagonist. It is notable for the absence of side effects associated with D2 or

₁-adrenergic receptor blockage. Early studies show that it is well-tolerated, and that it lowers Brief Psychiatric Rating Scale scores without significant neurological side effects.

Preliminary studies of ORG 5222, which binds to 5-HT_2A and D₂ receptors, demonstrate safety in low doses for healthy subjects (Andree et al., 1997). Further study regarding its therapeutic dosage and safety for a larger sample is required, according to Glick and Belanoff.

Among the currently available antipsychotics, Glick and Belanoff noted that quetiapine (Seroquel), a serotonin-dopamine antagonist, was the newest of the antipsychotics to be added to the armamentarium. However, Glick said, there are two other drugs used in Europe for schizophrenia that are not available in the United States: sertindole (Serlect) and flupentixol. Sertindole is available in 18 countries in Europe, but was recently taken off the market in England. In the United States, Abbott Laboratories withdrew its New Drug Application for sertindole in 1998 and closed down two ongoing U.S. clinical trials after the U.S. Food and Drug Administration stated it would require further clinical experience before granting approval. This action followed concern over a mild prolongation in the QT cardiac rhythm interval in a few sertindole-treated patients (Brown and Weaver, 1998).

Flupentixol is a D1 and D2 blocker. It has been shown to be better than placebo and equal to standard antipsychotics and to have fewer EPS than haloperidol (Haldol) (Glick et al., 1998). It is used in maintenance therapy with chronic schizophrenic patients whose main manifestations do not include excitement, agitation or hyperactivity.

In discussing the atypical antipsychotics (clozapine [Clozaril], olanzapine [Zyprexa], risperidone [Risperdal], quetiapine, sertindole and ziprasidone), Glick said they are equal in efficacy to the traditional antipsychotics "and their side effect profile seems to be better in that they [have] fewer extrapyramidal side effects and so far seem to show a much reduced propensity for tardive dyskinesia. In addition, they help [with the acute secondary] negative symptoms of schizophrenia, and they may improve cognitive functioning more than the typical antipsychotics. They also may improve mood disturbances in schizoaffective disorder."

Glick chaired an international group of experts sponsored by the International Pharmacology Algorithm Project (IPAP) to develop a new algorithm for treating schizophrenia (Pearsall et al., 1998). The IPAP effort was described as an attempt "to gather a consensus of clinical researchers from a variety of sites on the best current strategies for treating schizophrenia." (See related story on IPAP on page 63-Ed.)

"We are recommending atypicals as a first-line choice for almost everyone, unless there is a pressing reason not to use them, such as the patient is so agitated that you want to give an intramuscular preparation right away," Glick said. "None of the currently approved atypical antipsychotics has an IM formulation on the market, although ziprasidone IM is currently being tested. In addition, while many people believe that the atypical antipsychotics taken orally work just as fast as the conventional antipsychotics, others would argue that they don't. The definitive studies need to be done."

In the United States, clozapine is often described as the "prototypical atypical," Glick said. But it is being used more and more in Europe and "the incidence of fatalities secondary to agranulocytosis has been quite low...In some countries like Switzerland, for example, it is a first-line drug for schizophrenia; they don't wait for treatment-resistance to develop. But other [clinicians] say it is a very difficult drug to manage and, therefore, you should only use it after you have tried everything else." Glick added, "There is an honest difference of opinion."

Asked if there is a difference in efficacy among the atypical antipsychotics, Glick continued, "There haven't been enough well-designed and adequately controlled head-to-head trials to know which of the atypicals is better than another for a specific symptom." He added that there are some studies suggesting that risperidone and olanzapine are about equal in efficacy, a couple of studies suggesting that risperidone might be better than olanzapine in terms of its efficacy/side effect profile (Brecher and the Risperidone/Olanzapine Study Group, 1998), and some studies suggesting the olanzapine might be better than risperidone (Tran et al., 1997).

"I think the jury is out right now," he said. "More data [are] needed."

One of the surprises emerging from studies of atypical agents in various populations is that they seem to be efficacious for a variety of disorders. Sertindole, for example, is being used in different European countries for treatment of schizophrenia and schizoaffective disorders, major depressive episodes with psychosis, psychotic disorders due to medical conditions and psychosis in dementia, as well as for other indications in children, adolescents or in the elderly, Glick said. Clozapine also is being tried for other indications. Flupentixol is licensed for use in some countries in Europe as an antidepressant, and there are suggestions of its efficacy in the treatment of depression associated with impulse disorder (Glick et al., 1998).

Antidepressants

In their ACNP poster session, Glick and Belanoff also discussed drugs for mood and anxiety disorders. Among the new antidepressants on the market in the United States are nefazodone (Serzone), mirtazapine (Remeron) and citalopram (Celexa). Citalopram was approved by the FDA in July 1998.

Promising psychopharmacological agents available in Europe for depression include tianeptine (Ardix), a presynaptic serotonin uptake enhancer licensed in France, and reboxetine (Edronax, Pharmacia & Upjohn, Inc.), a selective noradrenaline reuptake inhibitor recently marketed in the United Kingdom. Reboxetine is currently in phase III clinical evaluation in the United States. With regard to tianeptine, Glick said there have been "some positive placebo-controlled studies for major depression [Ginestet, 1997] and some evidence of efficacy for chronic alcoholism."

Reboxetine has been shown to be equal in efficacy to tricyclic antidepressants and serotonin reuptake inhibitors with added benefits of few anticholinergic or sexual side effects. It has also been shown effective for various gradations of depression (including severe depression), and beneficial in increasing social functioning. At the ACNP meeting, the International Reboxetine Study Group reported on a study in which the drug was shown to be more effective than placebo in preventing relapse in patients with recurrent depression and to be well-tolerated in long-term treatment (Brown et al., 1998).

In the antidepressant pipeline is MK 869 (Merck & Co. Inc.), a substance P blocker. In animal studies, MK 869 has been shown to have a pronounced calming effect in guinea pigs. Clinical trials on its antidepressant efficacy are underway (Kramer et al., 1998; Nutt, 1998).

For bipolar disorder, new treatments include lamotrigine (Lamictal, Glaxo Wellcome Inc.); topiramate (Topamax, R.W. Johnson Pharmaceutical Research Institute), a sodium channel and GABAA modulator; and tiagabine (Gabitril, Abbott Laboratories), a GABA uptake inhibitor. Glick added that in the pipeline are vigabatrin (Sabril, Hoechst Marion Roussel Inc.), a GABA transamine inhibitor that is used to treat succinic semialdehyde dehydrogenase deficiency; oxcarbazepine (Novartis Pharmaceutical Corp.), a carbamazepine derivative that has fewer side effects; and zonisamide (Dainippon Pharmaceutical Co., Ltd.), an NA and T-type Ca blocker and weak carbonic anhydrase inhibitor that is used to treat epilepsy and has a mild side effect profile.

For anxiety disorders, Glick said abecarnil (Novartis Pharmaceuticals Corp.), a benzodiazepine partial agonist, is in the pipeline. It has been found to be a potentially beneficial short-term (<4 weeks) anxiolytic, though additional investigation is needed to determine efficacy for generalized anxiety disorder (Aufdem-brinke, 1998; Pollack et al., 1997). Two other drugs that are unlikely to come to the United States are amisulpride (Solian, Sanofi-Synthlabo), a D2 and D3 antagonist licensed in France that is used both as an antidepressant and as an antipsychotic, and moclobemide (Novartis Pharmaceutical Corp.), a reversible monoamine oxidase inhibitor licensed in most parts of Europe and in Canada.

"They are like orphan drugs," Glick said, "It's hard to say if they will be profitable."

Currently, Glick and his colleagues are involved in five different drug trials.

"We are looking at aripiprazole and ziprasidone. And we are part of the multinational clozapine study investigating whether clozapine can decrease the rate of suicide. Stephen Marder, M.D., [University of California, Los Angeles, School of Medicine and West Los Angeles Veterans Affairs Medical Center] and I are doing a study looking at [an] intramuscular depot preparation of conventional antipsychotics compared to the atypical antipsychotic Seroquel. These studies are a year or two away from publication."

Glick, along with John M. Davis, M.D., of the department of psychiatry, University of Illinois, Chicago, is conducting a secondary analysis "trying to figure out whether there is any difference in the data between industry-sponsored and nonindustry-sponsored drug trials." New research is mostly industry sponsored, which represents a major shift from the pioneering work conducted on typical antipsychotics. The FDA, as part of the drug approval process, requires most of the design features found within industry-sponsored trials, Glick said.

"The design is very rigidly mandated by the FDA, but there is only so much you can extrapolate. We need more studies coming from both industry and nonindustry sources."

Another problem in the development of pharmacological agents, according to Glick, is that it is "getting harder and harder to recruit patients for trials with antipsychotics." Glick said this is due in part to the development of the atypical antipsychotics and due in part to the persistence of attacks on psychiatric research in general, and on schizophrenia specifically because of the stigma associated with the disease. Additionally, he said, there are controversies surrounding the informed consent process.

"Patients with ulcers don't have a cognitive difficulty, so they can understand what is going on [in a clinical trial]," Glick said. But because of the cognitive difficulties of patients with schizophrenia, "there are very important limitations in conducting clinical trials of antipsychotics medications as well as precautions that must be taken."

Given the schizophrenic population's crucial need for better medications, Glick advocated that researchers continue to work collaboratively with consumer advocacy organizations to make the trials more accessible to patients and their families. Just as critical as the development of new psychotropic medications is the need to combine such medications with psychotherapy. Glick added that "the best way to insure compliance is to work with patients and their families doing psychoeducation."

Consumer education groups on schizophrenia, mood disorders and anxiety disorders meet regularly at Stanford Medical Center, according to Glick. As a routine part of his practice, Glick said he sees family members with patients on a regular basis.

"We give out a lot of literature [relevant to the patients' disorders] and use videos wherever possible," he said.

Glick also has been involved in controlled studies to determine whether psychoeducation makes a difference in medication compliance. John Clarkin, Ph.D., of Cornell University Medical College/New York Hospital-Cornell Medical Center, and Glick examined the effects of a psychoeducation intervention for married patients with bipolar disorders and their spouses (Clarkin et al., 1998). Patients were randomly assigned to receive either medication management or medication management plus a marital intervention with their spouses for an 11-month period. Patients' symptoms, functioning and adherence to their medication regimens were measured at study entry and at 11 months. The marital intervention was associated with improved medication adherence. The combined treatment did not affect the patients' symptom levels beyond the effects of the medication alone, but did result in significant incremental gains in overall patient functioning.

"Before that, [Clarkin, Gretchen Haas, Ph.D. (University of Pittsburgh), and] I did a large study of inpatient family intervention," Glick said. In that study (Glick et al., 1993), 169 hospitalized patients with psychiatric disorders and their families were randomly assigned to a medication plus psychoeducational inpatient family intervention or to a medication alone group. Patient and family outcome measures were assessed at admission and discharge and at six and 18 months after admission. Analysis of statistically significant differences in outcome suggested that inpatient family intervention was associated with clinically significant improvement at discharge, especially for female patients and patients with chronic schizophrenia and bipolar disorder.

The bottom line, according to Glick, is that "no matter how good a medicine is, it is no good unless somebody takes it."

References:

References

1.

Andree B, Halldin C, Vrijmoed-de Vries M, Farde L (1997), Central 5-HT2A and D2 dopamine receptor occupancy after sublingual administration of ORG 5222 in healthy men. Psychopharmacology (Berl) 131(4):339-345.

2.

Aufdembrinke B (1998), Abecarnil, a new beta-

3.

carboline, in the treatment of anxiety disorders. Br J Psychiatry Suppl (34):55-63.

4.

Brecher M, the Risperidone/Olanzapine Study Group (1998), Risperidone versus olanzapine in the treatment of patients with schizophrenia or schizoaffective disorder. Presented at the 37th annual meeting of the American College of Neuropsychopharmacology, Poster Session 128. Las Croabas, Puerto Rico. Dec.16.

5.

Brown A, Weaver R (1998), Promising new medications in development. NARSAD Research Newsletter Summer.

6.

Brown M, Montgomery SA, Versiani M (1998), Reboxetine is effective in preventing relapse and recurrence of major depressive disorder. Presented at the 37th annual meeting of the American College of Neuropsychopharmacology, Poster Session 84. Las Croabas, Puerto Rico. Dec. 16.

7.

Clarkin JF, Carpenter D, Hull J et al. (1998), Effects of psychoeducational intervention for married patients with bipolar disorder and their spouses. Psychiatr Serv 49(4):531-533.

8.

Ginestet D (1997), Efficacy of tianeptine in major depressive disorders with or without melancholia. Eur Neuropsychopharmacol Suppl 3:S341-S345.

9.

Glick ID, Belanoff JK, Ballon JS (1998), New psychotropic drugs for Axis I disorders: recently arrived, in development and never arrived. Presented at the 37th annual meeting of the American College of Neuropsychopharmacology, Poster Session 156. Las Croabas, Puerto Rico. Dec. 15.

10.

Glick ID, Clarkin JF, Haas GL, Spencer JH Jr. (1993), Clinical significance of inpatient family intervention: conclusions from a clinical trial. Hosp Community Psychiatry 44(9):869-873.

11.

Glick ID, Lecrubier Y, Montgomery SA et al. (1998), Promising psychopharmacological agents available in Europe. In: American Psychiatric Press Textbook of Psychopharmacology, Schatzberg A, Nemeroff CB, eds. Washington, D.C.: American Psychiatric Press.

12.

Inoue A, Miki S, Seto M et al. (1997), Aripiprazole, a novel antipsychotic drug, inhibits quinpirole-evoked GTPase activity but does not up-regulate dopamine D2 receptor following repeated treatment in the rat striatum. Eur J Pharmacol 321(1):105-111.

13.

Keck P Jr., Buffenstein A, Ferguson J et al. (1998), Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology (Berl) 140(2):173-184.

14.

Kramer MS, Cutler N, Feighner J et al. (1998), Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281(5383):1640-1645.

15.

Nutt D (1998), Substance-P antagonists: a new treatment for depression? Lancet 352(9141):1644-1646.

16.

Pearsall R, Glick ID, Pickar D et al. (1998), A new algorithm for treating schizophrenia. Psychopharmacol Bull 34(3):349-353.

17.

Pharmaceutical Research and Manufacturers of America (1998), 1998 Survey New Medicines in Development for Mental Illnesses. Washington, D.C.: Pharmaceutical Research and Manufacturers of America. June.

18.

Pollack MH, Worthington JJ, Manfro GG et al. (1997), Abecarnil for the treatment of generalized anxiety disorder: a placebo-controlled comparison of two dosage ranges of abecarnil and buspirone. J Clin Psychiatry 58(Suppl 11):19-23.

19.

Tran PV, Hamilton SH, Kuntz AJ et al. (1997), Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 17(5):407-418.