Amisulpride, an atypical antipsychotic marketed as Solian in Europe and Australia, is significantly more efficacious than first-generation antipsychotics, according to a meta-analysis that explored the efficacy of 10 second-generation antipsychotics (Davis et al., 2003). Yet, amisulpride is not in clinical trials in the United States, and Ira Glick, M.D., professor of psychiatry and behavioral sciences at the Stanford University School of Medicine, does not believe it will ever be. Amisulpride is just one of the many psychotropic drugs being marketed or developed in other regions of the world.

"There are a number of orphan drugs that won't come here. There is no money in it for the drug companies to bring them," Glick told Psychiatric Times Global Watch in an interview.

For their meta-analysis, Glick and colleagues collected clinical trial literature on patients with schizophrenia published between 1953 and 2002, as well as unpublished data (Davis et al., 2003). They received no financing from pharmaceutical companies for the study. They reviewed 124 controlled, randomized trials (18,272 patients) that compared conventional antipsychotics with atypical antipsychotics, and 18 studies (2,748 patients) of head-to-head comparisons between second-generation antipsychotics.

There are two findings from the meta-analysis, Glick noted: "One is that the second-generation agents clearly are better than the first-generation agents. They are slightly better for efficacy and clearly have a better side-effect profile, even with the questions about diabetes, lipids and long-term consequences. The second finding we were able to show is that of the second-generation agents, clozapine [Clozaril], amisulpride, risperidone [Risperdal] and olanzapine [Zyprexa] were significantly better than the first-generation agents."

The researchers reported statistically significant effect sizes for clozapine (0.49), amisulpride (0.29), risperidone (0.25) and olanzapine (0.21), compared to first-generation antipsychotics. Effect sizes were calculated from the Positive and Negative Syndrome Scale (PANSS), and when that was not available, from the Brief Psychiatric Rating Scale (BPRS). The effect sizes of amisulpride, risperidone and olanzapine correspond to 4 to 6 PANSS or 3 to 4 BPRS points.

Amisulpride was significantly better than the haloperidol (Haldol) comparator, regardless of the haloperidol dose, Glick said. He alluded to a study by Geddes and colleagues (2002) that questioned whether the improved efficacy of some atypical antipsychotics might be an artifact, due at least in part to the increasing side effects of higher than recommended doses of the comparator drug, haloperidol.

"There has been an issue that the haloperidol comparator was too high, but we analyzed it both ways, high dose and low dose, and we showed that amisulpride was better," explained Glick.

The meta-analysis also showed two head-to-head studies in which amisulpride was similar in efficacy to risperidone (Lecrubier, 2002; Lecrubier et al., 2000; Peuskens et al., 1999).

Atypical Antipsychotics

Other atypical antipsychotics reviewed in the meta-analysis that are not marketed in the United States were remoxipride, sertindole and zotepine. Remoxipride and sertindole, along with aripiprazole (Abilify), quetiapine (Seroquel) and ziprasidone (Geodon), showed similar efficacy to first-generation antipsychotics, in the sense that improvement scores were not statistically significantly better than those of first-generation antipsychotics. There was no clear evidence of superiority when comparing zotepine with first-generation antipsychotics in 12 studies, but there was some variability between the studies.

Amisulpride belongs to a group of drugs called the substituted benzamides, which also includes pimozide (Orap). It is a highly selective D 3 and D 2 receptor antagonist. Leucht and colleagues (2002) conducted a meta-analysis of 18 randomized, controlled trials comparing amisulpride with conventional antipsychotics or placebo. Amisulpride proved to be consistently more effective than conventional antipsychotics for global symptoms of schizophrenia (measured with the BPRS) and also for negative symptoms in 11 studies of acutely ill patients. It was also associated with lower use of antiparkinsonian medication and with fewer dropouts due to adverse events than conventional antipsychotics. In an analysis of 11 prospective, randomized amisulpride studies, amisulpride was associated with low weight gain: 0.8 kg (mean) at 10 weeks and 1.4 kg (mean) at one year (Leucht et al., 2003).

Adverse effects of amisulpride include insomnia, anxiety, agitation, drowsiness, gastrointestinal disorders, dry mouth, hyperprolactinemia and occasionally bradycardia.

Remoxipride, marketed as Roxiam in the United Kingdom, Denmark and Luxembourg, is also a substituted benzamide. It is a weak but selective D 2 receptor antagonist. Clinical trials have shown it to be an effective treatment for chronic schizophrenia and acute exacerbations of chronic schizophrenia. Improvement was found in both positive and negative symptoms. Pooled data from comparative trials with haloperidol showed a lower incidence of extrapyramidal symptoms (EPS), insomnia, tiredness, concentration difficulties and dry mouth in the remoxipride group. A new drug application (NDA) was filed for remoxipride in the United States but was withdrawn in 1993 due to reports of aplastic anemia and one death. The manufacturer, Astra Merck, Inc., has recommended restricting the use of the drug to patients who have failed other antipsychotics (Drug Facts and Comparisons, 2003).

Sertindole, a serotonin-dopamine antagonist, initially licensed in several European countries and South Africa as Serdolect and deemed approvable by the U.S. Food and Drug Administration, has had an equally challenging path. Following concerns over possible risks of cardiac dysrhythmias, the product was withdrawn throughout Europe. In the United States, Abbott Laboratories voluntarily withdrew its NDA for sertindole. In 2002, the European Commission lifted the suspension of Serdolect for the treatment of schizophrenia based on supplementary data substantiating the safety of the drug. H. Lundbeck A/S of Denmark, the patent holder, agreed to carry out a postmarketing study, and the company expects the drug to be available for general prescription and use in Europe in 2005. Side effects for sertindole include prolonged QT interval, peripheral edema, dry mouth, rhinitis, nasal congestion, dyspnea, paresthesia and abnormal ejaculation.

Zotepine, marketed as Zoleptil, Lodopin, Majorpin, Nipolept, Setous and Zopite, is a dopamine antagonist that has been in use in Japan since 1982 and Germany since 1990 (Green, 1999). It has a high affinity for D 1 - and D 2 -like receptors and for several serotonin receptors. Its ability to inhibit the reuptake of noradrenaline, together with its serotonergic activity, may explain its efficacy against negative symptoms (Green, 1999). In a 26-week, placebo-controlled trial (n=121), zotepine reduced the number of relapses in patients with chronic schizophrenia; the risk of recurrence was six times lower with zotepine than placebo. In addition, the level of EPS was no different between zotepine and placebo (Cooper et al., 2000a).

In a placebo-controlled comparison of zotepine versus chlorpromazine (Thorazine) in patients with acute exacerbation of schizophrenia (n=158), mean BPRS scores improved statistically significantly more with zotepine than chlorpromazine or placebo (Cooper et al., 2000b). Fenton and colleagues (2003) reviewed randomized trials to determine the effects of zotepine compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia. "Limited data suggest that zotepine is an antipsychotic, at least as effective as typical drugs ... Trials have not highlighted clear differences between zotepine and other atypical drugs," concluded the researchers. The most common adverse effects of zotepine are constipation, dry mouth, insomnia, dizziness, asthenia and weight gain.

Another drug for the treatment of schizophrenia not marketed in the United States is zuclopenthixol, a cis(Z)-isomer of clopenthixol, a neuroleptic of the thioxanthene group. It has a high affinity for dopamine D 1 and D 2 receptors and a high affinity for α1-adrenergic and 5HT 2 receptors. The drug is marketed throughout Europe, Latin America, Asia and the Middle East, as well as South Africa. There is one oral preparation (Clopixol, Cisordinol) and two depot forms: zuclopenthixol acetate (Clopixol-Acuphase; Cisordinol-Acutard) and zuclopenthixol decanoate (Clopixol Depot). Zuclopenthixol acetate is intended for use during acute psychotic episodes or exacerbation of psychosis associated with schizophrenia, when compliance with oral medication may be unreliable. Zuclopenthixol decanoate is intended for maintenance treatment of chronic schizophrenia in patients who have been stabilized with oral or other short-acting medication and who might benefit from transfer to longer-acting injectable therapy.

Fenton and colleagues (2001) reviewed controlled studies and unpublished data to estimate the effectiveness of zuclopenthixol acetate compared to other antipsychotics for the acute treatment of patients with schizophrenia or other psychotic illnesses who are having hallucinations or delusions. The researchers concluded that zuclopenthixol acetate was no more effective in controlling aggressive/disorganized behavior, acute psychotic symptoms or preventing side effects than other antipsychotics. The most common adverse events reported for this medication in clinical trials were drowsiness, fatigue, dizziness and EPS.

Iloperidone, which is a piperidinyl-benzisoxazole under development by Titan Pharmaceuticals, Inc., and Novartis Pharmaceuticals Corp., is currently in Phase III testing in 27 countries, including the United States. The atypical antipsychotic has a high 5HT 2A /D 2 binding ratio and a pharmacologic profile that is somewhat distinct from other molecules in its therapeutic class. For example, it has no affinity for histamine receptors, which may reduce the risk of sedation and weight gain.

At the 23rd Congress of the Collegium Internationale Neuro-Psychopharmacologicum (CINP), Fairweather and colleagues (2002) reported that iloperidone has similar efficacy but a significantly better side-effect profile than haloperidol in patients with schizophrenia and schizoaffective disorder. The multicenter, double-blind trial involved a primarily Asian population of patients with schizophrenia or schizoaffective disorder as defined by the DSM-IV. After 52 weeks, mean PANSS scores were reduced by 41% in patients treated with iloperidone and 38% in patients treated with haloperidol. Clinical Global Impression-Improvement (CGI-I) scores dropped by 73% in the iloperidone group and 60% in the haloperidol group. Patients receiving haloperidol experienced more EPS and had increases in serum prolactin levels. Serum prolactin levels were relatively unchanged in patients receiving iloperidone. A six-week electrocardiogram study of iloperidone found that the change in QT C internal for iloperidone was roughly comparable to that for ziprasidone, according to a press release by Titan Pharmaceuticals in 2002.

A limitation of atypical antipsychotics has been their lack of an injectable dosage form, but that is changing. In 2002, ziprasidone was the first atypical antipsychotic to have an injectable dosage form approved by the FDA. In February, Eli Lilly and Company reported that a rapid-acting intramuscular (IM) form of olanzapine for severely agitated patients with schizophrenia and bipolar disorder will be available in several countries early in 2004. It will be marketed as Zyprexa IM in Australia, Zyprexa Powder for Solution for Injection in the European Union, and Zyprexa IntraMuscular in Canada and the United States. Olanzapine IM was approved by the FDA on March 30 for treating acute agitation in schizophrenia and bipolar mania.

In a randomized, double-blind, placebo-controlled study, olanzapine IM was found to be superior to haloperidol in reducing agitation 15, 30 and 45 minutes after the first injection (Wright et al., 2001). Olanzapine IM was also statistically superior to placebo after two hours in clinical trials. Common adverse events included somnolence, dizziness and asthenia. In addition, clinical trials have shown olanzapine IM to be associated with infrequent decreases in blood pressure and heart rate that were not clinically significant.

A novel IM formulation of the atypical antipsychotic risperidone (Risperdal Consta) is currently available in more than 20 countries. In a 12-week, multicenter, double-blind study, patients with schizophrenia (n=400) were randomized to receive injections of placebo or long-acting risperidone (25 mg, 50 mg or 75 mg) once every two weeks (Kane et al., 2003). Significant improvement was seen at all doses studied in both positive symptoms and negative symptoms. An average of 45% of patients, depending on the dosage administered, had a ≥20% degree of symptom improvement with the IM formulation. The most common adverse effects reported were headache, upset stomach, restlessness, drowsiness, constipation, fatigue and dry mouth. In the United States, the IM formulation of risperidone is still under regulatory review.

Antidepressants

While reboxetine, a selective norepinephrine reuptake inhibitor, is not approved in the United States, it is widely sold in 50 countries. Reboxetine is marketed as Edronax in the United Kingdom, Norebox in Italy, and Irenor in Spain. Clinical trials have compared reboxetine with fluoxetine (Prozac) in the treatment of major depression (Andreoli et al., 2002; Kadhe et al., 2003; Massana et al., 1999). In these studies, reboxetine was comparable or more effective than fluoxetine. Massana and colleagues (1999) concluded that reboxetine was more effective than fluoxetine in patients with severe depression. In addition, it was more effective with regard to social functioning in patients who achieved remission. Andreoli and colleagues (2002) found that reboxetine and fluoxetine were more effective than placebo in the treatment of major depression and that both antidepressants were well tolerated but possessed different adverse-event profiles.

More recently, Fava and colleagues (2003) evaluated the efficacy and safety of an immediate switch to reboxetine in patients with depression unresponsive to fluoxetine. A statistically significant (p<0.001) improvement in the mean total 17-item Hamilton Rating Scale for Depression (HAM-D-17) score was seen from baseline by week 1 of reboxetine treatment with continued improvement at week 8. Clinical Global Impression-Improvement and CGI-Severity (CGI-S) scores were similarly improved. Adverse effects reported with reboxetine include dry mouth, dizziness, headache, insomnia, somnolence, tremor, agitation, hypotension and urinary hesitancy/retention. In the United States, Pharmacia filed an NDA for reboxetine, but did not gain approval as was expected in May 2001.

Milnacipran, a novel compound that exerts its effects by inhibiting reuptake of both norepinephrine and serotonin, is marketed as an antidepressant under the trade names Ixel and Toledomin in Europe, South America and Asia. In clinical studies, milnacipran showed an antidepressant efficacy similar to that of tricyclic antidepressants and selective serotonin reuptake inhibitors and superior to that of placebo (Delini-Stula, 2000). At the optimum dose of 100 mg/day, after four to eight weeks of treatment, 60% to 64% of in- or outpatients with major depression improved (≥50% reduction of HAM-D and Montgomery-Asberg Depression Rating Scale [MADRS] score) and about 32% to 39% of the patients achieved full remission (HAM-D score ≥7).

Results of a meta-analysis revealed that milnacipran (50 mg bid) was more effective in treating depression than fluoxetine (20 mg/day) or fluvoxamine (Luvox) (100 mg bid) (Lopez-Ibor et al., 1996). In a small, six-week study, Kanetani and colleagues (2003) found milnacipran to be safe and effective for the treatment of depression following mild-to-moderate traumatic brain injury.

Moclobemide, a reversible inhibitor of monoamine oxidase A, has been extensively evaluated in the treatment of a wide spectrum of depressive disorders. It is marketed in several countries as Aurorix and Manerix. Nearly all meta-analyses and most comparative studies indicated that in the acute management of depression moclobemide is more efficacious than placebo and as efficacious as TCAs (or some heterocyclic antidepressants) or SSRIs (Bonnet, 2003). There is growing evidence that moclobemide is not inferior to other antidepressants in treating subtypes of depression (e.g., dysthymia, endogenous [unipolar and bipolar], reactive, atypical, agitated and retarded depression). As with other antidepressants, limited evidence suggests that moclobemide has consistent long-term efficacy. For patients with bipolar depression, the risk of developing mania seems to be no higher with moclobemide than with other antidepressants.

Unlike irreversible MAO-inhibitors, moclobemide has a negligible propensity to induce hypertensive crisis after eating tyramine-rich food. Therefore, dietary restrictions are not as strict. Some adverse effects of moclobemide include dizziness, nausea and insomnia. Due to negligible anticholinergic and antihistaminic actions, moclobemide has been better tolerated than TCAs or heterocyclic antidepressants. Bonnet (2003) reported that gastrointestinal side effects and, especially, sexual dysfunction were much less frequent with moclobemide than with SSRIs.

Philipp and colleagues (2000) compared the emergent sexual effects of moclobemide and SSRIs during acute and maintenance therapy in routine practice. At baseline, six weeks, and three and six months of treatment, patients (n=268) were evaluated for sexual function using physician ratings and self-rating questionnaires. Incidences of impairments of sexual functioning with treatment, whether clinically relevant or not, were 24.3% with moclobemide and 61.5% with SSRIs (physician ratings). The researchers concluded that moclobemide should be considered a first-line antidepressant in patients for whom sexual function is important or sexual dysfunction is present.

In 2001, Organon filed an NDA for gepirone extended-release (ER), but the FDA asked for more efficacy information. Gepirone, a 5HT 1A receptor agonist, has been assessed for use in the treatment of depressive and anxiety disorders. Initial placebo-controlled clinical trials demonstrated that gepirone immediate-release (IR) improved symptoms of depression; however, its short half-life necessitated frequent administration, and high peak plasma concentrations at higher doses were associated with an increased incidence of adverse events (Robinson et al., 2003).

More attention is now being given to the gepirone ER. In a double-blind, eight-week trial, patients with a diagnosis of moderate-to-severe major depressive disorder (MDD) as defined by the DSM-IV and a baseline HAM-D-17 score ≥20 were randomized to gepirone ER (n=103) or placebo (n=106) (Feiger et al., 2003). The investigators concluded that gepirone ER "appears safe and effective in the short-term treatment of major depressive disorder and appears to be free of common side effects (e.g., weight gain, sexual dysfunction and sedation) seen with SSRIs." Common adverse events included dizziness, nausea and insomnia.

At the 156th Annual Meeting of the American Psychiatric Association, Davidson and Gibertini (2003) presented findings from a placebo-controlled trial showing that gepirone ER may have a positive effect on sexual function in patients with MDD. At the 43rd Annual New Clinical Drug Evaluation Unit (NCDEU) meeting, Ruwe and Gibertini (2003) found gepirone ER (40 mg/day to 80 mg/day) to be effective for relapse prevention in patients with recurrent major depression. The drug was also well tolerated during long-term treatment.

Pharmaceutical companies are now international entities and may have many medications in their R&D pipelines, not all of which will be available in every country for a variety of reasons. Mental health care professionals around the world can only hope that the best treatments are available to them, allowing their patients to receive the highest standard of care.

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