Моклобемид: Депрессия, әлеуметтік фобия және темекі тастауға көмекші дәрі

Antidepressant
Unipolar depression – Moclobemide has demonstrated effectiveness and efficacy in the treatment and management of major depressive disorder, with both endogenous and non endogenous depression responding; in addition moclobemide has a fast onset of action compared to other antidepressants and is significantly more tolerable than the tricyclic antidepressants. Due to a good safety profile and low incidence of side effects moclobemide is likely to have a high level of acceptability by individuals suffering from depression. Psychotic depression, unipolar endogenous depression, melancholic depression, retarded depression, agitated depression and neurotic depression all respond to moclobemide, as does atypical depression. Unipolar endogenous depression is reported to have the best response to moclobemide therapy. Individuals suffering from depression who are given moclobemide are twice as likely to improve on moclobemide than on placebo. A concern of antidepressant adverse effects is sexual dysfunction; however, moclobemide has been found to actually increase libido and improve impaired erection, ejaculation and orgasm. Cardiovascular toxicity is a concern with antidepressants such as tricyclic antidepressants as well as the irreversible MAOIs; when cardiovascular toxicity is a concern, SSRIs or the reversible MAOIs such as moclobemide are an option as they lack or have a significantly reduced level of cardiovascular toxicity in terms of adverse effect as well as in overdose. The effectiveness of moclobemide in agitated depression is equivalent to that of imipramine and sedative antidepressants such as amitriptyline, mianserin and maprotiline. The therapeutic response in agitated depressive individuals is similar to that seen in non agitated depression; however, a past history of use of antidepressants reduces the chance of successful therapeutic response. The addition of a benzodiazepine to moclobemide therapy has not been found to be of benefit in this population group. Moclobemide has better tolerability compared to TCAs. Social phobia – Moclobemide has been found to be effective for the treatment of social anxiety disorder in both short and long term placebo controlled clinical trials. Moclobemide is effective but not as effective as the irreversible MAOIs in the treatment of social phobia. Maximal benefits can take 8–12 weeks to manifest. There is a high risk of treatment failure if there is co morbid alcohol use disorder, however. The Australian Medicines Handbook lists social phobia as an accepted but not a licensed indication. The use of moclobemide in the treatment of social anxiety disorder has given mixed results with a tendency of response at higher doses (>300 mg/d) compared with placebo. Smoking cessation – Moclobemide has been tested in heavy dependent smokers against placebo based on the theory that tobacco smoking could be a form of self medicating of major depression, and moclobemide could therefore help increase abstinence rates due to moclobemide mimicking the MAO A inhibiting effects of tobacco smoke. A 2023 Cochrane review found only one 1995 trial Panic disorder is mentioned as an accepted but unlicensed indication in the Australian Medicines Handbook. Similar to other MAOIs, reversible MAOIs such as moclobemide may also be effective in a range of other psychiatric disorders. Menopausal flushing may also respond to moclobemide. In efficacy studies for the treatment of major depressive disorder, moclobemide has been found to be significantly more effective than placebo, as effective as the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), and somewhat less effective than the older, irreversible MAOIs phenelzine and tranylcypromine. In terms of tolerability, however, moclobemide was found to be comparable to the SSRIs and better tolerated than the TCAs and older MAOIs. There is some evidence that moclobemide on its own or in combination with other antidepressants such as SSRIs is also effective for treatment resistant depression and that the combination can be administered without the development of serotonin syndrome; however, further research is needed before such a combination can be recommended. Follow up studies show that ongoing use of antidepressants leads to continuing improvement in depression over time; and also have demonstrated that moclobemide retains its therapeutic efficacy as an antidepressant for at least a year. This long term efficacy is equivalent to that seen with other antidepressant classes. People on irreversible MAOIs have to discontinue these antidepressants two weeks before general anesthesia, however, the use of moclobemide, due to its reversible nature, would allow such patients to possibly continue antidepressant therapy. A dexamethasone suppression test (DST) and plasma and urine methoxyhydroxyphenylglycol (MHPG) test can be used to estimate who is likely to respond to moclobemide antidepressant therapy.

The doses of moclobemide in breast milk are very low (0.06% of moclobemide being recovered in breast milk) and therefore it has been concluded that moclobemide is unlikely to have any adverse effect on a suckling baby. Cognitive impairments have been found to improve in people with dementia when depression is treated with moclobemide. Due to the side effect profile of moclobemide, it may be a better option for this sub group of people than other antidepressants. Research has found evidence that moclobemide may be able to counter anti cholinergic (Scopolamine) induced cognitive impairments thus making moclobemide a good choice in the depression in the elderly and those with dementia.

Moclobemide is considered to be less toxic in overdose compared to older antidepressants, such as the tricyclic antidepressants and the irreversible and non selective MAOIs, Intoxications with moclobemide as single agent are usually mild; however, when combined with tricyclic or SSRI antidepressants the overdose is much more toxic and potentially fatal. Moclobemide, is preferred by doctors for patients who are at risk of suicide, due to moclobemide's low toxicity in overdose. Patients with mixed intoxications (e. g. with other CNS active drugs) may show severe or life threatening symptoms and should be hospitalized. Treatment is largely symptomatic and should be aimed at maintenance of the vital functions.

Withdrawal symptoms appear to be very rare with moclobemide compared to other antidepressants; a single report of relatively mild flu like symptoms persisting for 7 days after rapid reduction of high dose moclobemide therapy has been reported in one patient. Withdrawal of moclobemide causes a rebound in REM sleep. Discontinuation of moclobemide is recommended to be done gradually to minimise side effects (e. g. rapid return of condition being treated and/or the appearance of withdrawal symptoms). Tolerance to the therapeutic effects has been reported in a small number of users of MAOIs including moclobemide. which acts pharmacologically as a selective, reversible inhibitor of monoamine oxidase A (RIMA), a type of monoamine oxidase inhibitor (MAOI), and increases levels of norepinephrine (noradrenaline), dopamine, and especially serotonin in neuronal cells as well as in synaptic vesicles; extracellular levels also increase which results in increased monoamine receptor stimulation and suppression of REM sleep, down regulation of Beta 3 adrenergic receptors. Moclobemide's primary action is to disable MAO A enzymes from decomposing norepinephrine, serotonin, and dopamine which results in a rising level of these neurotransmitters. Although it has been estimated that a single 300 mg dose of Moclobemide inhibits 80% of monoamine oxidase A (MAO A) and 20 30% of MAO B, studies evaluating brain occupancy of MAO A enzymes have shown dosages of 600 mg to only inhibit 74% of MAO A enzymes and dosages in the 900–1200 mg range to inhibit slightly less MAO A than Phenelzine (Nardil) at 45–60 mg; subsequently, it is highly plausible that reports of lower efficacy could be largely or entirely the consequence of conservative dosage guidelines rather than the pharmacological properties of the drug. Previously, it was widely reported that both MAO A and MAO B enzymes were responsible for the metabolism of dopamine; however, new research suggests that MAO B enzymes are involved in the generation of GABA and not the degradation of dopamine. There is also some evidence of moclobemide possessing neuroprotective properties in rodent models. Inhibition of the serotonin metabolite is less pronounced than the norepinephrine metabolite which suggests there are other major metabolic pathways for serotonin other than MAO A. It has been described as a 'slow binding inhibitor', whereby conformational changes to either moclobemide or the enzyme to MAO A slowly form a more tightly bound complex, resulting in the non competitive MAO inhibition by moclobemide. The MAO inhibition of moclobemide lasts about 8–10 hours and wears off completely by 24 hours after dosing. Moclobemide suppresses the unstimulated release of certain proinflammatory cytokines which are believed to be involved in the pathophysiology of major depression and stimulates the release of anti inflammatory cytokines. Long term treatment with moclobemide leads to an increase in cyclic adenosine monophosphate (cAMP) binding to cAMP dependent protein kinase (PKA). Moclobemide is chemically unrelated to irreversible MAOI antidepressants and only has a very weak pressor effect of orally administered tyramine. In humans, the n oxide metabolites of moclobemide and moclobemide itself are the compounds that produce most of the inhibition of MAO A; other metabolites are significantly less potent than the parent compound. Moclobemide also has neuroprotective properties in its demonstrated anti hypoxia or anti ischemia effects; there is a possibility that moclobemide may possess similar neuro rescuing properties, similar to selegiline, however, research is required to determine this. Platelet MAO is of the MAO B and this is inhibited only to a small degree in humans; the inhibition is due to low levels of metabolites of moclobemide that have MAO B inhibiting properties. Moclobemide has been reported to be a mixed MAO A/MAO B inhibitor in rats but in man, it has been reported to be a pure MAO A inhibitor, blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. No reuptake inhibition of any of the neurotransmitters occurs. The pharmacodynamic action encompasses activation, elevation of mood, and improvement of symptoms like dysphoria, fatigue, and difficulties in concentration. The duration and quality of sleep may be improved. In the treatment of depression the antidepressant effect often becomes evident in the first week of therapy (earlier than typically noted with TCAs/SSRIs). MAO activity returns completely back to normal after 24 hours of the last dose, which allows for a quick switch to another antidepressant after the 24 hours. It is moderately bound to plasma proteins, especially albumin. Despite its short half life the pharmacodynamic action of a single dose persists for approximately 16 hours. The drug is almost completely metabolized in the liver; it is a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6 and CYP1A2. Less than 1 percent of the drug is excreted unchanged; 92 percent of the metabolised drug is excreted within the first 12 hours. The main metabolites are the N oxide Ro 12 5637 formed via morpholine N oxidation and lactam derivative Ro 12 8095 formed via morpholine C oxidation; active metabolites are found only in trace amounts. The unchanged drug (less than 1%) as well as the metabolites are excreted renally (in urine). The main degradation pathway of moclobemide is oxidation. About 44 percent of the drug is lost due to the first pass effect through the liver. Age and renal function do not affect the pharmacokinetics of moclobemide. However, patients with significantly reduced liver function require dose reductions due to the significant slowing of metabolism of moclobemide. Food slows the absorption but does not affect the bioavailability of moclobemide. Moclobemide has good penetration across the blood brain barrier with peak plasma levels within the central nervous system occurring 2 hours after administration.

Acute toxicity: The oral values in mouse and rat are quite high, indicating a wide therapeutic index. LD50 for mice is 730 mg/kg and for rats 1,300 mg/kg. In dogs doses in excess of 300 mg/kg led to vomiting, salivation, ataxia, and drowsiness. Chronic toxicity: In an 18 months study in rats with 10 mg/kg no signs of chronic toxicity were noted, with 50 mg/kg and 250 mg/kg only a slight loss of weight, and with 250 mg/kg mildly elevated Alkaline phosphatase and Gamma GT. Studies in dogs revealed no toxicity relevant for humans. No evidence for a possible hepatic or cardiovascular toxicity was found.

Irreversible MAOI antidepressants were discovered accidentally in the 1950s but their popularity declined as their toxicity especially their dangerous food interactions became apparent and rival tricyclic antidepressants were discovered. Reversible MAOIs were developed in the hope that they would exert efficacy in depressive disorders but with less of the toxicity of the older irreversible compounds; moclobemide's discovery and marketing brought the renewed interest in MAOIs due to an absence of dangerous tyramine food interactions and potent antidepressant effects. In 1992 moclobemide was launched onto the world markets. Moclobemide was the first reversible MAO A inhibitor to be widely marketed. Moclobemide as well as other newer antidepressants such as the SSRIs led to changes in prescribing patterns and broadened the treatment options for the management of depressive disorders. When moclobemide was discovered in 1972 in Switzerland, It was first approved in the UK and Europe as the first reversible and selective inhibitor of MAO A and is now approved in over 50 countries worldwide. and far superior to tricyclic antidepressants in terms of side effects, tolerability and overdose. With regard to effectiveness in the treatment of depression, moclobemide was determined to be as effective as all major antidepressant drug classes. There is no need for dietary restrictions in contrast to people on irreversible MAOIs and apart from an important interaction with other serotonergic enhancing agents such as SSRIs and pethidine, there are few serious drug interactions and because of these benefits, moclobemide became regarded as a beneficial addition to medical 'prescribing arsenal'. Additionally moclobemide was found, unlike most other antidepressants on the market, to actually improve all aspects of sexual function. It is the only reversible MAOI in use in clinical practice.

The Australian TGA approved moclobemide in December 2000. It is sold under many trade names worldwide including Apo Moclob, Apo Moclobemide, Auromid, Aurorix, Bei Su, Biorix, Depnil, Eutac, Hai Bei Lin, Langtian, Manerix, Mobemid, Moclamine, Moclo A, Moclobemid 1 A Pharma, Moclobemid AL, Moclobemid HEXAL, Moclobemid ratiopharm, Moclobemida, Moclobemida Genedec, Moclobemida Teva, Moclobemide Actavis, Moclobemide Aurobindo, Moclobemide CF, Moclobemide Mylan, Moclobemide Sandoz, Moclobemide Sopharma, Moclobemide Teva, Moclobemid neuraxpharm, Moclobemid ratiopharm, Moclobeta, Moclod, moclodura, Moclostad, Mocrim, Moklar, Teva Moclobemide, Tian Tai, Ya Zheng, and Zorix.