[The use of the monoamine oxidase inhibitor isocarboxazide in treatment-resistant depression]. / Anvendelse af monoaminooksidasehæmmeren isocarboxazid ved behandlingsresistent depression

The antidepressant efficacy of isocarboxazide is well established; however, the clinical use early became restricted and today the use of isocarboxazide in Denmark is very limited. Isocarboxazide is safe when keeping a low tyramine-containing diet and avoiding concomitant treatment with certain drugs. The risk of developing oedema can be reduced by vitamin B6 treatment. Normal dosage isocarboxazide may be prescribed for all patients because isocarboxazide is not metabolized through the CYP2D6 enzyme complex like most other antidepressants. It is recommended to include isocarboxazide in the official treatment algorithms for patients who are resistant to conventional antidepressant therapy and electroconvulsive therapy.

The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver I2 imidazoline-preferring receptors.

1. The binding of [3H]-idazoxan in the presence of 10(-6) M (-)-adrenaline was used to quantitate I2 imidazoline-preferring receptors in the rat brain and liver after chronic treatment with various irreversible and reversible monoamine oxidase (MAO) inhibitors. 2. Chronic treatment (7-14 days) with the irreversible MAO inhibitors, phenelzine (1-20 mg kg-1, i.p.), isocarboxazid (10 mg kg-1, i.p.), clorgyline (3 mg kg-1, i.p.) and tranylcypromine (10 mg kg-1, i.p.) markedly decreased (21-71%) the density of I2 imidazoline-preferring receptors in the rat brain and liver. In contrast, chronic treatment (7 days) with the reversible MAO-A inhibitors, moclobemide (1 and 10 mg kg-1, i.p.) or chlordimeform (10 mg kg-1, i.p.) or with the reversible MAO-B inhibitor Ro 16-6491 (1 and 10 mg kg-1, i.p.) did not alter the density of I2 imidazoline-preferring receptors in the rat brain and liver; except for the higher dose of Ro 16-6491 which only decreased the density of these putative receptors in the liver (38%). 3. In vitro, phenelzine, clorgyline, 3-phenylpropargylamine, tranylcypromine and chlordimeform displaced the binding of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors from two distinct binding sites. Phenelzine, 3-phenylpropargylamine and tranylcypromine displayed moderate affinity (KiH = 0.3-6 microM) for brain and liver I2 imidazoline-preferring receptors; whereas chlordimeform displayed high affinity (KiH = 6 nM) for these receptors in the two tissues studied, Clorgyline displayed very high affinity for rat brain (KiH = 40 pM) but not for rat liver I2 imidazoline-preferring receptors (KiH = 169 nM). 4. Preincubation of cortical or liver membranes with phenelzine (10-4 M for 30 min) did not alter the total density of I2 imidazoline-preferring receptors, indicating that this irreversible MAO inhibitor does not irreversibly bind to I2 imidazoline-preferring receptors. In contrast, preincubation with 10-6 Mclorgyline reduced by 40% the Bmax of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors.5. Chronic treatment (7 days) with the inducers of cytochrome P-450 enzymes phenobarbitone (40 or 80 mg kg-1, i.p.), 3-methylcholanthrene (20 mg kg-1, i.p.) or 2-methylimidazole (40 mg kg-1, i.p.) did not alter the binding parameters of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors.The compound SKF 525A, a potent inhibitor of cytochrome P-450 enzymes which forms a tight but reversible complex with the haemoprotein, completely displaced with moderate affinity (KiH = 2-10 microM)the specific binding of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors. Preincubation of total liver homogenates with 3 x 10-4 M phenelzine in the presence of 10-3 M NADH, a treatment that irreversibly inactivates the haeme group of cytochrome P-450, did not reduce the density of liver I2 imidazoline-preferring receptors. These results discounted a possible interaction of [3H]-idazoxan with the haeme group of cytochrome P-450 enzymes.6. Together the results indicate that the down-regulation of I2 imidazoline-preferring receptors is associated with an irreversible inactivation of MAO (at least in the brain) that is not related either to the affinity of the MAO inhibitors for I2 imidazoline-preferring receptors or to an irreversible binding to these putative receptors. These findings indicate a novel effect of irreversible MAO inhibitors in the brain and suggest a new target for these compounds that could be of relevance in the treatment of depression, a disease in which an increased density of brain I2 imidazoline-preferring receptors has been reported.

Influence of higher rates of agitation on release patterns of immediate-release drug products.

The dissolution procedure serves as a quality control test to assure batch-to-batch uniformity and bioequivalence of a product once the bioavailability of the product has been established. It can also be used to detect manufacturing and/or process variations that could reduce product bioavailability. Dissolution testing must be conducted at an appropriate agitation rate. Tests conducted at high agitation rates may lose the ability to differentiate between good and bad products. Although the effect of high agitation rates has been known for some time, several immediate-release drug products still have United States Pharmacopeia (USP) monograph dissolution procedures that require very high agitation rates. A systematic survey was conducted on marketed tablets of chloroquine phosphate, griseofulvin, hydroxychloroquine sulfate, isocarboxazide, primaquine phosphate, and sulfadiazine. Each of these products has a USP monograph requiring a dissolution test at a paddle speed of 100 rpm. To study the influence of agitation rate on the dissolution rate of these products, dissolution studies were conducted at paddle speeds of 50, 75, and 100 rpm with the USP apparatus 2 (paddle method). The dissolution rate increased with an increase in the agitation rate from 50 to 75 rpm. However, no significant increase in the dissolution rate was noted with an increase in the agitation rate from 75 to 100 rpm. The data support the position that the higher agitation rate of 100 rpm is not necessary for a quality control procedure or a compendial standard for the products tested.

Central nervous system toxicity after abrupt monoamine oxidase inhibitor switch: a case report.

DESCRIPTION: There have been numerous case reports of adverse reactions involving monoamine oxidase inhibitors (MAOIs), including reactions that developed when one MAOI was substituted for another. Although most reports have usually described a switch from isocarboxazid or phenelzine to tranylcypromine, we report a case of acute central nervous system toxicity possibly associated with a switch from phenelzine to isocarboxazid. SYMPTOMATOLGY: Predominant symptoms included stuporous sensorium, hypertension, tachycardia, tremor, and urinary retention. Onset of symptoms began within 48 hours after the abrupt MAOI switch. CONCLUSIONS: Clinicians must allow a sufficient washout period before adding any agent that has a known potential to interact adversely with MAOIs. In addition, patients who are unusually sensitive to one type of MAOI may also be at increased risk for developing problems with a different MAOI secondary to unforeseen pharmacokinetic or pharmacodynamic effects, even at doses that are usually considered subtherapeutic.

Efficacy of combined antidepressant therapy in resistant neurotic disorder.

A 35-year-old woman with persistent affective and phobic symptoms responded dramatically to a combination of isocarboxazid and amitriptyline, and this improvement was maintained over the next three-and-a-half years. Isocarboxazid was replaced by placebo, using double-blind procedure. The change to placebo was accompanied by a marked increase in anxiety and depressive symptoms, which resolved when active isocarboxazid was reintroduced. It is suggested that combined antidepressant therapy still has a place in the treatment of resistant neurotic disorder.

Neuroleptic malignant syndrome: a case report with post-mortem brain and muscle pathology.

The neuroleptic malignant syndrome is a rare but dangerous complication of treatment with neuroleptics. The aetiology and pathophysiology of the syndrome are reviewed, and a fatal case is presented where both brain and muscle pathology are described. Striking myopathic changes in this case, accompanied by only minimal and non-specific brain abnormalities, support a peripheral rather than central mechanism for the hyperthermia.

The response of depressed inpatients to isocarboxazid.

Fifty-six inpatients with unipolar depression completed treatment with isocarboxazid. In comparing the differences between responders and nonresponders, it was found that psychomotor retardation, pathological guilt, daily persistence of unremitting symptoms, phobic anxiety, dexamethasone suppression test nonsuppression, and neuroticism were significantly more common among nonresponders. Reactivity of mood, blaming others, and extraversion were more common in responders. Total endogenous depression scores on the Newcastle 1, Newcastle 2, and Michigan scales were also significantly higher in nonresponders. Attained platelet monoamine oxidase inhibition was similar in both groups.

A comparative evaluation of three discriminant scales for endogenous depression.

Three discriminant scales for diagnosing endogenous depression were examined in 56 depressed inpatients. These scales were the Newcastle 1 (N1), Newcastle 2 (N2), and Michigan Index (MI). The scales agreed on diagnosis in 17 (30%) patients; respective frequencies of endogenous depression were 23%, 57%, and 78% for the N2, N1, and MI scales. Relationships were examined between treatment response to isocarboxazid, drug dose, and diagnostic type for each scale. Significant dose X diagnosis interactions were noted for N1 and N2, but not for MI. A correlational within-dose analysis of all three scales revealed that actual diagnostic score was related to outcome only for high-dose patients on the Newcastle-1 scale; no other significant correlations emerged.

The importance of dose in isocarboxazid therapy.

Little information is available on the effectiveness and safety of particular doses of isocarboxazid. In a study using isocarboxazid doses of 30 and 50 mg/day in depressed inpatients, the higher dose was well tolerated and did not result in any greater toxicity than the 30 mg dose. Significantly greater elevation of plasma serotonin (Week 2) and platelet MAO inhibition were seen with 50 mg/day. In nonmelancholic depressions, 50 mg proved to be more effective than 30 mg in symptoms of depression and anxiety. However, this did not apply to the vegetative-physiologic symptoms of depression.

MAO inhibitor therapy in trichotillomania associated with depression: case report.

Trichotillomania may sometimes be an atypical variant of depressive illness. A case is reported in which the MAO inhibitor isocarboxazid was successfully used to treat both depression and associated trichotillomania. The symptoms recurred upon discontinuation of the drug and were ameliorated by reintroduction of isocarboxazid .

An evaluation of two doses of isocarboxazid in depression.

Two fixed doses of isocarboxazid were studied over a 4-week period in depressed in-patients. Thirty-five patients completed treatment, 20 of whom received 30 mg isocarboxazid per day, and 15 of whom received 50 mg isocarboxazid per day. No overall difference between the two doses was observed. When patients were subdivided into melancholia/endogenous depression or non-melancholia/non-endogenous depression, the higher dose exerted significantly greater antidepressant effects in the latter groups. Diagnostic type is considered to be an important variable in studies of dose-effect relationships with antidepressant drugs. The side effects of isocarboxazid at the two doses studied did not differ materially, although there was a suggestion of greater anticholinergic effect at 50 mg.

Controlled trial of trimipramine, monoamine oxidase inhibitors, and combined treatment in depressed outpatients.

A study was carried out in which 135 mildly or moderately depressed outpatients were randomly allocated to one of five groups receiving six weeks' treatment weith antidepressant drugs. The groups received a tricyclic antidepressant (trimipramine; mean dose 106 mg at night) or a monoamine oxidase inhibitor (MAOI) (phenelzine or isocarboxazid; mean doses 45 and 32 mg/day respectively), or a combination of the two (phenelzine plus trimipramine or isocarboxazid plus trimipramine). Various scales were used to measure depression before and at one, three, and six weeks of treatment, and results were assessed blindly. The tricyclic antidepressant was found to be consistently superior to the MAOIs and the combined treatments. Some differential indicators of response to the various antidepressants were found--for example, patients with initial complaints of dizziness, suicidal ideas, irritability, and insomnia and a longer duration of illness were more likely to respond to trimipramine--but these were of only modest significance. Side effects were not troublesome in any group. It is concluded that neither MAOIs nor MAOIs combined with tricyclic antidepressants are the treatment of first choice in unselected outpatients with mild or moderate depression.

[Treatment of a case of grave orthostatic hypotension (Shy-Drager's syndrome) by an association of L-dopa and mono-amine-oxidase inhibitor (author's transl)]. / Syndrome de Shy et Drager: traitement d'une hypotension orthostatique grave par l'association L.dopa-inhibiteur de la mono-amine oxydase.

The authors report a case of grave orthostatic hypotension (Shy-Drager's syndrome) with major postural disturbances. The biological test confirmed a catecholaminergic deficiency. After several drugs were tried unsucessfully, an association of L-Dopa and fractionated doses of mono-amine-oxydase inhibitor was proposed. The increase blood pressure was sufficient to block the diturbances of postural adaptation, without inducing hypertensive jerks. The functionnal result have been stable for three years, while the parkinsonian syndrome have shown little progression.

[Central effects of beta-phenylethylamines. (8). Increase in spontaneous motor activities of mice caused by intracerebrally administered metaramino].

Metaraminol (MA) (40, 80 and 160 microng) was injected i.c. into mice and spontaneous motor activity (SMA) measured by photo-cell counters method was found to increase 30 min after the injection. Ninety min after, the SMA was restored to the saline treated control. MA (80 microng i.c.) was also injected into isocarboxazide (Iso) pretreated mice and the SMA markdly increased as compared with the Iso+saline treated group or tween+MA treated group. When MA was injected i.c. into alpha-methyl-p-tyrosine (alpha-MT) pretreated mice, the SMA significantly increased as compared with that of the alpha-MT+saline treated group, but there was a decrease as compared with that of the tween+saline or tween+MA treated group. In alpha-MT treated mice. L-Dopa restored the hyper-motor activity of animals treated with MA. Diethyldithiocarbamate (700mg/kg i.p.) had no influence, whereas haloperidol markedly blocked the hyper-motor activity induced by MA. The hyper-motor activity induced by MA in mice raised the question of a possible role of noradrenaline and dopamine in the mediation of this action.