Diagnostic pitfalls of drug-induced immune hemolytic anemia.

Immune hemolytic anemia (IHA) is a rare complication of drug administration. However, its true incidence remains obscure, as there are a number of factors that may lead to misdiagnosis. The clinical and serologic pictures are variable, and there is a great deal of unawareness that certain drugs can cause IHA. Furthermore, serologic results can be easily misinterpreted, resulting in a wrong diagnosis.

Intravenous self-administration of nomifensine in rats: implications for abuse potential in humans.

Rats acquired and maintained intravenous self-administration of nomifensine, a new antidepressant compound. Additional experiments implicated dopamine-containing neurons in this behavior. These findings, along with the marked pharmacological similarities between nomifensine and such drugs as cocaine and methylphenidate, indicate a potential for nomifensine abuse by humans.

Treatment of bulimia with nomifensine.

The authors treated 12 consecutive bulimic patients with nomifensine, a novel antidepressant recently approved for American use. Two patients developed fever, necessitating discontinuation of the drug. Of the other 10 patients, nine showed moderate or better improvement, with strikingly few side effects.

Double-blind comparison of the efficacy and safety of nomifensine maleate vs. placebo in depressed outpatients.

Nomifensine maleate in doses of 100-200 mg/day was compared to placebo in a double-blind study of 50 moderately to severely depressed outpatients seen in a private practice. Efficacy ratings over the 28-day treatment period revealed significant improvement in the nomifensine group on the Hamilton Depression Rating Scale and Clinical Global Impressions, as well as the Self-Rating Symptom Scale, Brief Psychiatric Rating Scale, and Hamilton Anxiety Scale. These differences in favor of nomifensine were seen as early as Day 7 of treatment and were generally consistent throughout the trial. No clinically meaningful changes in vital signs or laboratory values were found over the course of treatment. Only one side effect, a pruritic rash in one patient, was directly attributable to active drug treatment. The CGI Therapeutic Index revealed a very favorable ratio of clinical benefit to side effects for nomifensine maleate.

Multicenter placebo-controlled evaluation of nomifensine treatment in depressed outpatients.

Outpatients aged 18-65 who met Feighner et al. criteria for primary affective disorder-depression and had Hamilton Depression Rating Scale (HDRS) scores greater than or equal to 20 were randomly assigned to receive nomifensine (N = 61) or placebo (N = 63) for 4 weeks. On all measures of efficacy (HDRS, Clinical Global Impressions, Hopkins Symptom Check List, Brief Psychiatric Rating Scale), patients treated with nomifensine showed significant improvement compared to placebo patients; improvement was evident after 1 week on some scales. No clinically important changes were seen over the course of treatment in findings of physical examinations, ECGs, and clinical laboratory evaluations. Side effects associated with active treatment were mild to moderate in severity and rarely led to cessation of therapy. Thus, significant clinical improvement was seen in these moderately to severely depressed outpatients, without significant adverse experiences.

Double-blind placebo-controlled multicenter evaluation of the efficacy and safety of nomifensine in depressed outpatients.

Outpatients with primary affective disorder-depression who scored at least 20 on the Hamilton Depression Rating Scale (HDRS) were randomly assigned to treatment for 1 month with nomifensine (100-200 mg/day) or placebo. Clinical laboratory and physical evaluations, including ECGs when feasible, revealed no clinically significant changes over the course of treatment. Nomifensine patients showed improvement compared to placebo on the HDRS total score endpoint analysis (p = .06) and the Cognitive Disturbance and Retardation factors (p less than or equal to .05). A better rate of improvement was seen with nomifensine on the Clinical Global Impressions severity of illness (p less than or equal to .05) and therapeutic index (p less than or equal to .05) components. No differences were seen between groups in the incidence of overall or specific side effects. Nomifensine thus appeared safe and superior to placebo on several key measures of depressive symptomatology in this multicenter study of depressed outpatients.

Nomifensine in the treatment of depressed geriatric patients.

In a randomized double-blind study, the efficacy and safety of nomifensine and amitriptyline were compared in 33 geriatric patients with endogenous and reactive depression. Significant improvement was noted over the 4-week study period for all groups on the Clinical Global Impression, Hamilton, and Plutchik rating scales. There was significantly more improvement among the patients with reactive depression treated with nomifensine and among the patients with endogenous depression treated with amitriptyline, as assessed by the Plutchik Geriatric Rating Scale.

Epilepsy, antidepressants, and the role of nomifensine.

The clinical and animal literature on the relationship between antidepressant drugs and the precipitation of seizures or lowering of the seizure threshold is reviewed. All tricyclic antidepressants have the potential to provoke seizures, particularly in patients with a preexisting lowered seizure threshold. A pilot investigation and a double-blind trial comparing the nontricyclic nomifensine with amitriptyline and placebo in epileptic patients are described. Results of these and other studies suggest that nomifensine--almost alone among the antidepressant drugs--has minimal seizure-provoking effects and therefore may be valuable in the management of patients with epilepsy or other neurologic diseases associated with lowered seizure threshold.

Multicenter double-blind comparison of nomifensine and imipramine for efficacy and safety in depressed outpatients.

Nomifensine, a tetrahydroisoquinoline antidepressant, was compared with imipramine in a 4-week multicenter double-blind study of depressed outpatients (100 on nomifensine, 56 on imipramine). Nomifensine was at least as effective as imipramine in reducing depressive symptoms at average doses of 150 mg/day. When significant differences did occur on Hamilton Depression Rating Scale scores, they favored nomifensine for improvement in cognitive symptoms and interest in work and activities. Early in treatment, nomifensine patients also showed a better relationship between clinical response and side effects. The proportions of patients experiencing at least one side effect or dropping out due to side effects were almost twice as high in the imipramine group. Dry mouth and sedating effects were 2-3 times more frequent among imipramine patients. Thus, nomifensine demonstrated clinical efficacy at least comparable with imipramine but with indications of a more favorable side effects profile.

Nomifensine vs. imipramine in depressed inpatients.

In a double-blind random assignment study, nomifensine was compared to imipramine in a population of depressed male inpatients (N = 36; ages 22-56 years). Nomifensine and imipramine in doses of 100-150 mg/day were found to be comparable over the 4-week treatment period on the Hamilton Depression Rating Scale and Clinical Global Impressions. The Self-Rating Symptom Scale showed differences favoring nomifensine for the Depression factor at Days 3, 7, and 10. In extensive laboratory analyses, no clinically important changes were seen within or between groups. Although differences were not significant, more discomforting side effects--specifically, anticholinergic, nervousness/restlessness, and sedation--were seen in the imipramine than the nomifensine group. These results indicate that nomifensine compares favorably with imipramine in the treatment of depressed inpatients.

Nomifensine in geriatric inpatients: a placebo-controlled study.

In a double-blind randomized group design, nomifensine (100 mg single daily dose) was compared to placebo in 100 geriatric inpatients (average age = 75 years). Patients in each group were categorized as depressed (Feighner criteria for primary depressive disorder and Hamilton Depression Rating Scale scores greater than or equal to 18) or non-depressed (no psychopathologic disorders and HDRS scores less than or equal to 7). Outcome measures included the HDRS and various tests of cognitive function. The nomifensine-treated depressed patients showed significant improvement over the placebo depressed patients early in and throughout treatment. Depressed patients also showed significant improvement on several cognitive tests with nomifensine treatment. Nomifensine was well tolerated in both depressed and nondepressed patients.

A two-center double-blind study of nomifensine, imipramine, and placebo in depressed geriatric outpatients.

Both nomifensine and imipramine were superior to placebo in a 4-week double-blind study involving 63 geriatric patients (greater than 60 years) with primary affective disorder-depression. Significant improvement in the active drug groups was demonstrated on the Hamilton Depression Rating Scale, Clinical Global Impressions, Brief Psychiatric Rating Scale, and Hopkins Symptom Check List. Analysis of laboratory and physical examination data, including ECGs, revealed no clinically significant changes associated with either drug. Compared to the imipramine group, nomifensine-treated patients showed a more rapid rate of improvement and a lower incidence of discomforting side effects.

A double-blind comparative evaluation of the efficacy and safety of nomifensine, imipramine, and placebo in depressed geriatric outpatients.

Nomifensine, imipramine, and placebo were compared in 61 depressed geriatric outpatients over a 35-day period. At average daily doses of 150 mg, nomifensine and imipramine were significantly more effective than placebo in reducing symptoms of depression in this sample of elderly depressed patients. Nomifensine and imipramine were generally comparable in clinical effect; 78% of the nomifensine-treated patients were rated as improved at the end of treatment as compared with 64% of imipramine and 20% of placebo patients. The findings suggest a more favorable side effect profile for nomifensine, which was associated with a lower frequency of sedating and anticholinergic effects than was seen in the imipramine group.

Pooling 12 nomifensine studies for efficacy generalizability.

Twelve parallel group, randomized, double-blind studies of nomifensine's safety and efficacy in the treatment of depressed patients were combined into three pools according to common protocols. This approach permitted evaluation of 1) efficacy results for studies with moderate-sized pools of patients, 2) the degree to which efficacy was generalizable to depressed patients in the general population, and 3) the conditions under which pooled active vs. active (imipramine vs. nomifensine) studies could be regarded as pivotal in support of efficacy. Results showed that nomifensine's superiority over placebo was generalizable to patients with a wide range of characteristics, including age 60 years or older. An appropriate statistical profile of more pronounced nomifensine responders would include patients with a duration of present episode less than 4 months who are acutely depressed, exhibit more severe symptoms, and have been previously hospitalized or treated with other psychotropic medications. A comprehensive assessment and power analysis of the pooled active vs. active studies provided strong evidence for comparability of nomifensine and imipramine.

An overview of side effects and long-term experience with nomifensine from United States clinical trials.

During the clinical development of nomifensine maleate (Merital), 1319 depressed patients received nomifensine (average doses of 150 mg/day) in 4-6 week trials; treatment was continued for at least 2 months in 170 patients and at least 6 months in 53. Comparison data were provided by 593 patients who received placebo and 612 given the tricyclic antidepressant imipramine HCl (average doses of 150 mg/day). The relationship of therapeutic gain to interfering side effects (the therapeutic index) was rated by the investigators and nomifensine received a more favorable therapeutic index rating than did imipramine. Side effect information was collected at each visit. Nomifensine produced less sedating, anticholinergic, and other discomforting side effects than imipramine and was able to sustain clinical benefit with minimal side effects in patients treated up to 6 months.

A review of the clinical safety and tolerability of nomifensine.

The tolerability and safety of nomifensine in clinical practice are reviewed in the context of relevant topics for the second-generation antidepressants. Nomifensine is nonsedating and impairs neither psychomotor nor cognitive performance. It has minimal anticholinergic-like properties and is nontoxic to the heart and cardiovascular system at therapeutic dosage. It is nonepileptogenic. There are few relevant drug interactions, and overdose data to date show no serious sequelae resulting from the drug itself. Side effects include sleep disturbance, restlessness, and nausea; rare adverse reactions are in keeping with other antidepressants. Nomifensine's profile differentiates it from other commonly used antidepressants; the implications of this for treatment of both common depressions and specific at-risk patients are discussed.

The new generation antidepressants: promising innovations or disappointments?

"New generation" antidepressants are generally considered to include all agents introduced in recent years which are neither tricyclic in structure nor monoamine oxidase inhibitors. They include the tetracyclics (mianserin and maprotiline), the bicyclic serotonergic compounds (fluoxetine and citalopram), and the unicyclics (bupropion), as well as the triazolobenzodiazepine derivatives (alprazolam), the triazolopyridines (trazodone) and the tetrahydroisoquinolines (nomifensine). Methodologic and economic considerations have hampered attempts to develop agents with significantly greater specificity or safety than traditional agents. Traditional agents, while lacking specificity, do have extensive records of efficacy and long-term safety and are usually less expensive than new agents. Patients not responding to traditional agents often have medical or characterologic problems that exclude them from participating in controlled studies of new agents. These problems are discussed and potential approaches to the development of new agents are presented.

Pharmacology of nomifensine: a review of animal studies.

Nomifensine has demonstrated efficacy in several animal models that have been found to be predictive of clinical antidepressant activity, and has also been found to have a low potential for both cardiovascular and anticholinergic side effects. A comparison of nomifensine's profile with those of standard antidepressant agents shows this drug to possess clear advantages which may make it an attractive choice for the treatment of endogenous depression.

Immune haemolytic anaemia and nomifensine treatment in north west England 1984-85: report of six cases.

Nomifensine, an antidepressant used for eight years in Britain, was particularly popular in the north west of England. Haemolytic anaemia was recognised as a rare side effect, but in 1984 a cluster of six cases was referred to the North West Regional Transfusion Centre, reflecting an incidence of 0.006%. These were collected within 18 months and showed variable serological features, indicating that antibodies associated with nomifensine treatment are neither rare nor of one particular type. The accumulation of this and similar data contributed to its withdrawal from the British market in January, 1986.

Second generation antidepressants: a comparative review.

The authors review four "second generation" antidepressants (maprotiline, amoxapine, trazodone, and nomifensine) in terms of action on biogenic amines and receptors, antidepressive efficacy, and adverse effects. Doxepin is used as a comparative agent and is similar to the prototypical tricyclic agents in all the above categories. Maprotiline is a selective noradrenergic agent, but shares a similar adverse effect profile with doxepin and may be associated with a high frequency of seizures in overdose. Amoxapine is a mixed action antidepressant with significant neuroleptic activity in vivo. Its adverse effect profile is highlighted by symptoms related to its neuroleptic activity, and seizures and acute renal failure in overdose. Trazodone is a selective serotonergic agent with low anticholinergic activity, and minimal morbidity/mortality in overdose. Reports of priapism, leading to impotence in some men, however, is of concern. Nomifensine is a potent noradrenergic and dopaminergic agent with low anticholinergic activity, and minimum cardiotoxicity and low morbidity/mortality in overdose. Its most important adverse effects include overstimulation and infrequent, usually reversible, immunologic hypersensitivity reactions. Trazodone and nomifensine have favorable profiles for use in the elderly. Trazodone may be more favorable in the anxious/agitated patient due to its sedative effects, whereas nomifensine may be more beneficial in the retarded, apathetic patient.