Moclobemide: Difference between revisions
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{{ | {{Drugbox | ||
| verifiedrevid = | | Verifiedfields = changed | ||
| IUPAC_name = | | verifiedrevid = 457784738 | ||
| image = | | IUPAC_name = 4-chloro-''N''-(2-morpholin-4-ylethyl)benzamide | ||
| width = | | image = Moclobemide.svg | ||
| image2 = | | width = 250 | ||
| width2 = | | image2 = Moclobemide3Dan.gif | ||
| width2 = 225 | |||
<!--Clinical data--> | <!--Clinical data--> | ||
| Drugs.com = {{drugs.com|CONS| | | tradename = Amira, Aurorix, Clobemix, Depnil, Manerix | ||
| | | Drugs.com = {{drugs.com|CONS|moclobemide}} | ||
| pregnancy_AU = B3 | |||
| legal_AU = S4 | |||
| legal_CA = Rx-only | |||
| legal_UK = POM | |||
| legal_status = | | legal_status = | ||
| routes_of_administration = | | routes_of_administration = oral | ||
<!--Pharmacokinetic data--> | <!--Pharmacokinetic data--> | ||
| bioavailability = | | bioavailability = 55-95% (increases with repeat administration)<ref>{{cite journal|last=Fitton|first=A|author2=Faulds, D |author3=Goa, KL |title=Moclobemide. A review of its pharmacological properties and therapeutic use in depressive illness|journal=Drugs|date=April 1992|volume=43|issue=4|pages=561–596|pmid=1377119|doi=10.2165/00003495-199243040-00009}}</ref><ref name = Lancet/> | ||
| protein_bound = | | protein_bound = 50%<ref name = Lancet/><ref name = MAOA>{{cite journal|last=Schoerlin|first=MP|author2=Mayersohn, M |author3=Korn, A |author4= Eggers, H |title=Disposition kinetics of moclobemide, a monoamine oxidase-A enzyme inhibitor: single and multiple dosing in normal subjects|journal=Clinical Pharmacology and Therapeutics|date=October 1987|volume=42|issue=4|pages=395–404|pmid=3665338}}</ref> | ||
| metabolism = [[ | | metabolism = [[Hepatic]]<ref>{{cite journal|last=Jauch|first=R|author2=Griesser, E |author3=Oesterhelt, G |author4=Arnold, W |author5=Meister, W |author6=Ziegler, WH |author7= Guentert, TW |title=Biotransformation of moclobemide in humans|journal=Acta Psychiatrica Scandinavica Supplementum|year=1990|volume=82|issue=S360|pages=87–90|pmid=2248086|doi=10.1111/j.1600-0447.1990.tb05344.x}}</ref><ref name = kinetics>{{cite journal|last=Guentert|first=TW|author2=Tucker, G |author3=Korn, A |author4=Pfefen, JP |author5=Haefelfinger, P |author6= Schoerlin, MP |title=Pharmacokinetics of moclobemide after single and multiple oral dosing with 150 milligrams 3 times daily for 15 days|journal=Acta Psychiatrica Scandinavica Supplementum|year=1990|volume=82|issue=S360|pages=91–93|doi=10.1111/j.1600-0447.1990.tb05345.x|pmid=2248087}}</ref> | ||
| | | elimination_half-life = 1-2 hours,<ref name = kinetics /> 4 hours (elderly)<ref name = Lancet>{{cite journal|last=Freeman|first=H|date=December 1993|title=Moclobemide|journal=Lancet|volume=342|issue=8886-8887|pages=1528–1532|doi=10.1016/S0140-6736(05)80090-X|pmid=7902906}}</ref><ref>{{cite journal|last=Gex-Fabry|first=M|author2=Balant-Gorgia, AE |author3=Balant, LP |title=Potential of concentration monitoring data for a short half-life drug: analysis of pharmacokinetic variability for moclobemide|journal=Therapeutic Drug Monitoring|date=February 1995|volume=17|issue=1|pages=39–46|pmid=7725375|doi=10.1097/00007691-199502000-00007}}</ref> | ||
| excretion = [[ | | excretion = [[Renal]], [[Faeces|Faecal]] (<5%)<ref name = MAOA /> | ||
<!--Identifiers--> | <!--Identifiers--> | ||
| CAS_number_Ref = {{cascite|correct|??}} | | CAS_number_Ref = {{cascite|correct|??}} | ||
| CAS_number = | | CAS_number = 71320-77-9 | ||
| ATC_prefix = | | ATC_prefix = N06 | ||
| ATC_suffix = | | ATC_suffix = AG02 | ||
| PubChem = 4235 | |||
| PubChem = | |||
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | ||
| DrugBank = | | DrugBank = DB01171 | ||
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ||
| ChemSpiderID = | | ChemSpiderID = 4087 | ||
| UNII_Ref = {{fdacite|correct|FDA}} | | UNII_Ref = {{fdacite|correct|FDA}} | ||
| UNII = | | UNII = PJ0Y7AZB63 | ||
| KEGG_Ref = {{keggcite|correct|kegg}} | | KEGG_Ref = {{keggcite|correct|kegg}} | ||
| KEGG = | | KEGG = D02561 | ||
| ChEBI_Ref = {{ebicite| | | ChEBI_Ref = {{ebicite|changed|EBI}} | ||
| ChEBI = | | ChEBI = 83531 | ||
| ChEMBL_Ref = {{ebicite|correct|EBI}} | | ChEMBL_Ref = {{ebicite|correct|EBI}} | ||
| ChEMBL = | | ChEMBL = 86304 | ||
<!--Chemical data--> | <!--Chemical data--> | ||
| C= | | C=13 | H=17 | Cl=1 | N=2 | O=2 | ||
| molecular_weight = | | molecular_weight = 268.739 g/mol | ||
| smiles = | | smiles = Clc1ccc(cc1)C(=O)NCCN2CCOCC2 | ||
| InChI = 1/ | | InChI = 1/C13H17ClN2O2/c14-12-3-1-11(2-4-12)13(17)15-5-6-16-7-9-18-10-8-16/h1-4H,5-10H2,(H,15,17) | ||
| InChIKey = YHXISWVBGDMDLQ-UHFFFAOYAU | |||
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | ||
| StdInChI = 1S/ | | StdInChI = 1S/C13H17ClN2O2/c14-12-3-1-11(2-4-12)13(17)15-5-6-16-7-9-18-10-8-16/h1-4H,5-10H2,(H,15,17) | ||
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | ||
| StdInChIKey = | | StdInChIKey = YHXISWVBGDMDLQ-UHFFFAOYSA-N | ||
}} | }} | ||
'''Moclobemide''' (sold as '''Amira''', '''Aurorix''',<ref name="pmid8023056">{{cite journal |author=Scheen AJ |title=[Drug of the month. Moclobemide (Aurorix)] |language=French |journal=Rev Med Liege |volume=49 |issue=5 |pages=291–2 |date=May 1994 |pmid=8023056 }}</ref> '''Clobemix''' , '''Depnil''' and '''Manerix'''<ref name="pmid7905288"/>) is a [[Reversible inhibitor of monoamine oxidase A|reversible]] [[monoamine oxidase inhibitor]] (MAOI) drug primarily used to treat [[Clinical depression|depression]] and [[social anxiety]].<ref name="pmid8875133"/><ref name = AMH/><ref name = BNF/> It is not approved for use in the United States,<ref name="pmid10063483"/> but is approved in other Western countries such as the [[United Kingdom|UK]]<ref name = BNF/> and [[Australia]] ([[Therapeutic Goods Administration|TGA]] approved in December 2000).<ref name = SANDOZ/> It is produced by affiliates of the [[Hoffmann–La Roche]] pharmaceutical company. Initially, Aurorix was also marketed by Roche in [[South Africa]], but was withdrawn after its patent rights expired and [[Cipla]] Medpro's Depnil and Pharma Dynamic's Clorix became available at half the cost. | |||
{{ | |||
== | No significant rise in blood pressure occurs when moclobemide is combined with amines such as [[tyramine]] containing foods or pressor amine drugs, unlike the older non-selective irreversible MAOIs which cause a severe rise in blood pressure with such combination.<ref name="pmid8875133"/> Due to the lack of [[anticholinergic]], [[cardiovascular]], cognitive and psychomotor impairments moclobemide is advantageous in the elderly as well as those with cardiovascular disease.<ref name="pmid8875133"/> | ||
==Medical uses== | |||
Reversible selective MAOIs such as moclobemide are widely underprescribed due to the misconception that the side effect profile of moclobemide is analogous to that of the irreversible and non-selective MAOIs.<ref name="pmid9074307"/> MAOIs such as moclobemide are reported to have a relatively fast onset of action compared to other antidepressant drug classes,<ref name="pmid1609114">{{cite journal |author=Cesura AM, Pletscher A |title=The new generation of monoamine oxidase inhibitors |journal=Prog Drug Res |volume=38 |issue= |pages=171–297 |year=1992 |pmid=1609114 |doi=10.1007/978-3-0348-7141-9_3}}</ref> and have good long-term tolerability in terms of side effects.<ref name="pmid1394027"/> | |||
Tolerance does not seem to occur; research has found that moclobemide retains its beneficial therapeutic properties in depression for at least a year.<ref name="Amrein-1993">{{Cite journal | last1 = Amrein | first1 = R. | last2 = Hetzel | first2 = W. | last3 = Stabl | first3 = M. | last4 = Schmid-Burgk | first4 = W. | title = RIMA--a new concept in the treatment of depression with moclobemide | journal = Int Clin Psychopharmacol | volume = 7 | issue = 3–4 | pages = 123–32 |date=Jan 1993 | pmid = 8468432 | doi=10.1097/00004850-199300730-00001}}</ref> | |||
*[[Major Depressive Disorder|Unipolar depression]]. Moclobemide has demonstrated effectiveness and efficacy in the treatment and management of [[major depressive disorder]],<ref name="pmid7980178">{{cite journal |author=Mitchell PB, Mitchell MS |title=The management of depression. Part 2. The place of the new antidepressants |journal=Aust Fam Physician |volume=23 |issue=9 |pages=1771–3, 1776–81 |date=September 1994 |pmid=7980178 }}</ref> 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.<ref name="pmid2248063">{{cite journal |author=Lecrubier Y, Guelfi JD |title=Efficacy of reversible inhibitors of monoamine oxidase-A in various forms of depression |journal=Acta Psychiatr Scand Suppl |volume=360 |issue= |pages=18–23 |year=1990 |pmid=2248063 }}</ref> Due to a very good safety profile and very low incidence of side effects moclobemide is likely to have a high level of acceptability by individuals suffering from depression.<ref name="pmid1609337"/> Higher doses (>450 mg/day) may be more effective in severe depression, while patients treated with a lower dose tend to respond less well than those treated with [[tricyclic antidepressants]].<ref>{{cite journal|last=Angst|first=J|author2=Amrein, R |author3=Stabl, M |title=Moclobemide and tricyclic antidepressants in severe depression: meta-analysis and prospective studies|journal=Journal of Clinical Psychopharmacology|date=August 1995|volume=15|issue=4 Suppl 2|page=16S–23S|pmid=7593725|doi=10.1097/00004714-199508001-00004}}</ref> | |||
== | : [[Psychotic depression]], unipolar [[endogenous depression]], [[melancholic depression]], [[retarded depression]], [[agitated depression]] and [[neurotic depression]] all respond to moclobemide.<ref name="pmid7717094">{{cite journal |author=Priest, RG; Gimbrett, R; Roberts, M; Steinert, J |title=Reversible and selective inhibitors of monoamine oxidase A in mental and other disorders |journal=Acta Psychiatr Scand Suppl |volume=386 |issue= |pages=40–3 |year=1995 |doi=10.1111/j.1600-0447.1995.tb05923.x |pmid=7717094 }}</ref> As does [[atypical depression]].<ref name="pmid8440808">{{cite journal |author=Spoov J, Suominen JY, Lahdelma RL, et al. |title=Do reversed depressive symptoms occur together as a syndrome? |journal=J Affect Disord |volume=27 |issue=2 |pages=131–4 |date=February 1993 |pmid=8440808 |doi=10.1016/0165-0327(93)90086-Y}}</ref> Unipolar [[endogenous depression]] is reported to have the best response to moclobemide therapy.<ref name="Angst-1993">{{Cite journal | last1 = Angst | first1 = J. | last2 = Scheidegger | first2 = P. | last3 = Stabl | first3 = M. | title = Efficacy of moclobemide in different patient groups. Results of new subscales of the Hamilton Depression Rating Scale | journal = Clin Neuropharmacol | volume = 16 Suppl 2 | pages = S55–62 | year = 1993 | pmid = 8313398 }}</ref><ref name="Woggon-1993">{{Cite journal | last1 = Woggon | first1 = B. | title = The role of moclobemide in endogenous depression: a survey of recent data | journal = Int Clin Psychopharmacol | volume = 7 | issue = 3–4 | pages = 137–9 |date=Jan 1993 | pmid = 8468434 | doi=10.1097/00004850-199300730-00003}}</ref> Individuals suffering from depression who are given moclobemide are twice as likely to improve on moclobemide than on [[placebo]].<ref name="Silverstone-1993">{{Cite journal | last1 = Silverstone | first1 = T. | title = Moclobemide--placebo-controlled trials | journal = Int Clin Psychopharmacol | volume = 7 | issue = 3–4 | pages = 133–6 |date=Jan 1993 | pmid = 8468433 | doi=10.1097/00004850-199300730-00002}}</ref> A concern of antidepressant adverse effects is sexual dysfunction; however, moclobemide has actually been found to increase the libido and also improve impaired erection, ejaculation and orgasm.<ref name="pmid8468436">{{cite journal |author=Philipp M, Kohnen R, Benkert O |title=A comparison study of moclobemide and doxepin in major depression with special reference to effects on sexual dysfunction |journal=Int Clin Psychopharmacol |volume=7 |issue=3–4 |pages=149–53 |date=January 1993 |pmid=8468436 |doi=10.1097/00004850-199300730-00005}}</ref> 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.<ref name="pmid8353831">{{cite journal |author=Tikal K, Hrabánková M |title=[Indications for antidepressive agents in relation to diseases of the cardiovascular system] |language=Czech |journal=Cesk Psychiatr |volume=89 |issue=3 |pages=163–5 |date=June 1993 |pmid=8353831 }}</ref> | ||
: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.<ref name="pmid8557884">{{cite journal |author=Delini-Stula A, Mikkelsen H, Angst J |title=Therapeutic efficacy of antidepressants in agitated anxious depression--a meta-analysis of moclobemide studies |journal=J Affect Disord |volume=35 |issue=1–2 |pages=21–30 |date=October 1995 |pmid=8557884 |doi=10.1016/0165-0327(95)00034-K}}</ref> | |||
* [[Bipolar depression]]. While not generally recommended as a monotherapy for bipolar depression (as with all antidepressants) in one clinical trial it appeared (although statistical significance at the p=0.05 was not reached) as though moclobemide was equally effective as [[imipramine]] at reducing depressive symptoms, but had a significantly lower risk of causing a manic switch.<ref name = BPD>{{cite journal|title=Moclobemide vs. imipramine in bipolar depression: a multicentre double-blind clinical trial|doi=10.1034/j.1600-0447.2001.00240.x|date=August 2001|volume=104|issue=2|pages=104–109|pmid=11473503|author=Silverstone, T|journal=Acta Psychiatrica Scandinavica}}</ref> This is in line with recent findings that [[monoamine oxidase inhibitors|MAOIs]] as a class are superior to other antidepressants (in terms of both their relatively low rate of manic switching and their efficacy) in the treatment of bipolar depression.<ref>{{cite journal|last=Mallinger|first=AG|author2=Frank, E |author3=Thase, ME |author4=Barwell, MM |author5=Diazgranados, N |author6=Luckenbaugh, DA |author7= Kupfer, DJ |title=Revisiting the effectiveness of standard antidepressants in bipolar disorder: are monoamine oxidase inhibitors superior?|journal=Psychopharmacology Bulletin|year=2009|volume=42|issue=4|pages=64–74|pmid=19629023|pmc=3570273}}</ref> | |||
*[[Dysthymia]]; moclobemide has been found to be effective in the treatment and management of this depressive disorder.<ref name="pmid19698626">{{cite journal |author=Versiani M, Nardi AE, Figueira I |title=Pharmacotherapy of dysthymia: review and new findings |journal=Eur. Psychiatry |volume=13 |issue=4 |pages=203–9 |date=July 1998 |pmid=19698626 |doi=10.1016/S0924-9338(98)80005-9 }}</ref> | |||
*[[Social anxiety disorder|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.<ref name="pmid8923114">{{cite journal |author=Nutt D, Montgomery SA |title=Moclobemide in the treatment of social phobia |journal=Int Clin Psychopharmacol |volume=11 Suppl 3 |issue= |pages=77–82 |date=June 1996 |pmid=8923114 |doi=10.1097/00004850-199606000-00013}}</ref> Moclobemide is effective but not as effective as the irreversible MAOIs in the treatment of social phobia.<ref>{{cite pmid | 22436306}}</ref> Maximal benefits can take 8 – 12 weeks to manifest.<ref name="pmid1393304">{{cite journal |author=Versiani M, Nardi AE, Mundim FD, Alves AB, Liebowitz MR, Amrein R |title=Pharmacotherapy of social phobia. A controlled study with moclobemide and phenelzine |journal=Br J Psychiatry |volume=161 |issue= 3|pages=353–60 |date=September 1992 |pmid=1393304 |doi=10.1192/bjp.161.3.353}}</ref> There is a high risk of treatment failure if there is co-morbid [[alcohol abuse]], however.<ref name="pmid9466158">{{cite journal |author=Versiani M, Amrein R, Montgomery SA |title=Social phobia: long-term treatment outcome and prediction of response--a moclobemide study |journal=Int Clin Psychopharmacol |volume=12 |issue=5 |pages=239–54 |date=September 1997 |pmid=9466158 |doi=10.1097/00004850-199709000-00001}}</ref> The [[Australian Medicines Handbook]] lists social phobia as an accepted but not a licensed indication.<ref name = AMH>{{cite isbn|9780980579093}}</ref> | |||
*[[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]],<ref name="Berlin-1995">{{Cite journal | last1 = Berlin | first1 = I. | last2 = Saïd | first2 = S. | last3 = Spreux-Varoquaux | first3 = O. | last4 = Launay | first4 = JM. | last5 = Olivares | first5 = R. | last6 = Millet | first6 = V. | last7 = Lecrubier | first7 = Y. | last8 = Puech | first8 = AJ. | title = A reversible monoamine oxidase A inhibitor (moclobemide) facilitates smoking cessation and abstinence in heavy, dependent smokers | journal = Clin Pharmacol Ther | volume = 58 | issue = 4 | pages = 444–52 |date=Oct 1995 | doi = 10.1016/0009-9236(95)90058-6 | pmid = 7586937 }}</ref> and moclobemide could therefore help increase abstinence rates due to moclobemide mimicking the MAO-A inhibiting effects of [[tobacco smoke]]. Moclobemide was administered for 3 months and then stopped; at 6 months follow-up it was found those who had taken moclobemide for 3 months had a much higher successful quit rate than those in the placebo group. However, at 12-month follow-up the difference between the placebo group and the moclobemide group was no longer significant.<ref name="Hughes-2007">{{Cite journal | last1 = Hughes | first1 = JR. | last2 = Stead | first2 = LF. | last3 = Lancaster | first3 = T. | title = Antidepressants for smoking cessation | journal = Cochrane Database Syst Rev | issue = 1 | pages = CD000031 | year = 2007 | doi = 10.1002/14651858.CD000031.pub3 | pmid = 17253443 }}</ref> | |||
*[[Panic disorder]]. Moclobemide is useful in the treatment and management of panic disorder.<ref name="pmid9466172">{{cite journal |author=Tiller JW, Bouwer C, Behnke K |title=Moclobemide for anxiety disorders: a focus on moclobemide for panic disorder |journal=Int Clin Psychopharmacol |volume=12 Suppl 6 |issue= |pages=S27–30 |date=October 1997 |pmid=9466172 |doi=10.1097/00004850-199710006-00006}}</ref> Panic disorder is mentioned as an accepted but unlicensed indication in the Australian Medicines Handbook.<ref name = AMH /> | |||
*[[Attention Deficit Hyperactivity Disorder|ADHD]]. Two small studies assessing the benefit of moclobemide in people with attention deficit disorder found that moclobemide produced favourable results.<ref name="pmid7717094"/> | |||
*[[Fibromyalgia]], moclobemide has been found to improve pain and functioning in this group of people.<ref name="Heymann-">{{Cite journal | last1 = Heymann | first1 = RE. | last2 = Paiva | first2 = Edos S. | last3 = Helfenstein | first3 = M. | last4 = Pollak | first4 = DF. | last5 = Martinez | first5 = JE. | last6 = Provenza | first6 = JR. | last7 = Paula | first7 = AP. | last8 = Althoff | first8 = AC. | last9 = Souza | first9 = EJ. | last10 = Neubarth | first10 = Fernando | last11 = Lage | first11 = Lais Verderame | last12 = Rezende | first12 = Marcelo Cruz | last13 = Assis | first13 = Marcos Renato de | last14 = Lopes | first14 = Maria Lucia Lemos | last15 = Jennings | first15 = Fabio | last16 = Araújo | first16 = Rejane Leal C. da Costa | last17 = Cristo | first17 = Valéria Valim | last18 = Costa | first18 = Evelin Diana Goldenberg | last19 = Kaziyama | first19 = Helena Hideko S. | last20 = Yeng | first20 = Lin Tchia | last21 = Iamamura | first21 = Marta | last22 = Saron | first22 = Thais Rodrigues Pato | last23 = Nascimento | first23 = Osvaldo J. M. | last24 = Kimura | first24 = Luiz Koiti | last25 = Leite | first25 = Vilnei Mattioli | last26 = Oliveira | first26 = Juliano | last27 = Araújo | first27 = Gabriela Tannus Branco de | last28 = Fonseca | first28 = Marcelo Cunio Machado | title = Brazilian consensus on the treatment of fibromyalgia | journal = Rev Bras Reumatol | volume = 50 | issue = 1 | pages = 56–66 | year = 2010| doi = 10.1590/S0482-50042010000100006| pmid = 21125141 }}</ref> | |||
*[[Migraine]]. Moclobemide has been reported to be effective in the treament of migraine and [[chronic tension headache]].<ref name="pmid8349478">{{cite journal |author=Claman JM |title=The potential effectiveness of moclobemide, the new monoamine oxidase inhibitor, in the prophylaxis of migraine |journal=Headache |volume=33 |issue=6 |pages=339 |date=June 1993 |pmid=8349478 |doi=10.1111/j.1526-4610.1993.hed3306339.x}}</ref><ref name="pmid9324719">{{cite journal |author=Meienberg O, Amsler F |title=[Preventive treatment of migraine and chronic tension headache with moclobemide] |language=German |journal=Praxis (Bern 1994) |volume=86 |issue=27–28 |pages=1107–12 |date=July 1997 |pmid=9324719 }}</ref> | |||
Similar to other MAOIs, reversible MAOIs such as moclobemide may also be effective in a range of other psychiatric disorders.<ref name="pmid7717094"/><ref name="pmid2248064">{{cite journal |author=Liebowitz MR, Hollander E, Schneier F, et al. |title=Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders |journal=Acta Psychiatr Scand Suppl |volume=360 |issue= |pages=29–34 |year=1990 |pmid=2248064 |doi=10.1111/j.1600-0447.1990.tb05321.x}}</ref> [[Menopausal]] flushing may also respond to moclobemide.<ref name="pmid7915384">{{cite journal |author=Menkes DB, Thomas MC, Phipps RF |title=Moclobemide for menopausal flushing |journal=Lancet |volume=344 |issue=8923 |pages=691–2 |date=September 1994 |pmid=7915384 |doi=10.1016/S0140-6736(94)92131-8}}</ref> Moclobemide may also have benefit for some patients with Parkinson's Disease by extending and enhancing the effects of [[l-dopa]].<ref name="pmid7593732">{{cite journal |author=Sieradzan K, Channon S, Ramponi C, Stern GM, Lees AJ, Youdim MB |title=The therapeutic potential of moclobemide, a reversible selective monoamine oxidase A inhibitor in Parkinson's disease |journal=J Clin Psychopharmacol |volume=15 |issue=4 Suppl 2 |pages=51S–59S |date=August 1995 |pmid=7593732 |doi=10.1097/00004714-199508001-00010}}</ref> | |||
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.<ref name="pmid10063483">{{cite journal | doi = 10.1016/S0893-133X(98)00075-X | author = Lotufo-Neto F., Trivedi M., Thase M.E. | year = 1999 | title = Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression |url = http://www.nature.com/npp/journal/v20/n3/pdf/1395258a.pdf | format = PDF | journal = Neuropsychopharmacology | volume = 20 | issue = 3| pages = 226–247 | pmid = 10063483 }}</ref> 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.<ref name="pmid8875133"/><ref name="pmid8968657">{{cite journal |author=Baumann P |title=Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors |journal=Clin Pharmacokinet |volume=31 |issue=6 |pages=444–69 |date=December 1996 |pmid=8968657 |doi=10.2165/00003088-199631060-00004}}</ref> 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.<ref name="pmid9074307">{{cite journal |author=Kennedy SH |title=Continuation and maintenance treatments in major depression: the neglected role of monoamine oxidase inhibitors |journal=J Psychiatry Neurosci |volume=22 |issue=2 |pages=127–31 |date=March 1997 |pmid=9074307 |pmc=1188835 }}</ref> | |||
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.<ref name="pmid1546140">{{cite journal |author=Hill S, Yau K, Whitwam J |title=MAOIs to RIMAs in anaesthesia--a literature review |journal=Psychopharmacology (Berl.) |volume=106 Suppl |issue= |pages=S43–5 |year=1992 |pmid=1546140 |doi=10.1007/bf02246234}}</ref><ref name="Blom-Peters-1993">{{Cite journal | last1 = Blom-Peters | first1 = L. | last2 = Lamy | first2 = M. | title = Monoamine oxidase inhibitors and anesthesia: an updated literature review | journal = Acta Anaesthesiol Belg | volume = 44 | issue = 2 | pages = 57–60 | year = 1993 | pmid = 8237297 }}</ref> | |||
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.<ref name="pmid8488751">{{cite journal |author=Alevizos B, Hatzimanolis J, Markianos M, Stefanis CN |title=Clinical, endocrine and neurochemical effects of moclobemide in depressed patients |journal=Acta Psychiatr Scand |volume=87 |issue=4 |pages=285–90 |date=April 1993 |pmid=8488751 |doi=10.1111/j.1600-0447.1993.tb03373.x}}</ref> | |||
===Pregnancy and lactation=== | |||
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.<ref name="pmid7905288"/> | |||
===Children=== | |||
Use in children is not recommended as there is insufficient data to assess their safety and efficacy in these patients.<ref name = AMH/><ref name = BNF/> | |||
===Elderly=== | |||
Reversible MAOIs such as moclobemide may have advantages in the treatment of depression associated with [[Alzheimer's disease]] due to its effect on noradrenaline.<ref name="pmid1546130">{{cite journal |author=Chan-Palay V |title=Depression and senile dementia of the Alzheimer type: a role for moclobemide |journal=Psychopharmacology (Berl.) |volume=106 Suppl |issue= |pages=S137–9 |year=1992 |pmid=1546130 |doi=10.1007/bf02246259}}</ref> Cognitive impairments have been found to improve in people with dementia when depression is treated with moclobemide.<ref name="pmid7717094"/> Due to its superior safety profile, moclobemide has been recommended as a first line agent for the treatment of depression in the elderly.<ref name="pmid2248077">{{cite journal |author=De Vanna, M; Kummer, J; Agnoli, A; Gentili, P; Lorizio, A; Anand, R|title=Moclobemide compared with second-generation antidepressants in elderly people |journal=Acta Psychiatr Scand Suppl |volume=360 |issue= |pages=64–6 |year=1990 |pmid=2248077 }}</ref> Due to the side effect profile of moclobemide, it may be a better option for this sub group of people than other antidepressants.<ref name="pmid1546128">{{cite journal |author=Tiller JW |title=Post-stroke depression |journal=Psychopharmacology (Berl.) |volume=106 Suppl |issue= |pages=S130–3 |year=1992 |pmid=1546128 |doi=10.1007/bf02246257}}</ref> Research has found evidence that moclobemide may be able to counter cholinergic induced cognitive impairments thus making moclobemide a good choice in the depression in the elderly and those with dementia.<ref name="pmid2248080">{{cite journal |author=Wesnes K, Anand R, Lorscheid T |title=Potential of moclobemide to improve cerebral insufficiency identified using a scopolamine model of aging and dementia |journal=Acta Psychiatr Scand Suppl |volume=360 |pages=71–2 |year=1990 |pmid=2248080 }}</ref> | |||
==Adverse effects== | |||
The incidence of adverse events is not correlated with age; however, adverse events occur more often in females than in males.<ref name="pmid7593736">{{cite journal |author=Guentert TW, Banken L, Hilton S, Holford NH |title=Moclobemide: relationships between dose, drug concentration in plasma, and occurrence of adverse events |journal=J Clin Psychopharmacol |volume=15 |issue=4 Suppl 2 |pages=84S–94S |date=August 1995 |pmid=7593736 |doi=10.1097/00004714-199508001-00014}}</ref> Moclobemide is regarded as a generally safe antidepressant and due to its favorable side effect profile, it can be considered a first-line therapeutic antidepressant.<ref name="pmid7622819">{{cite journal |author=Swinkels JA, de Jonghe F |title=Safety of antidepressants |journal=Int Clin Psychopharmacol |volume=9 Suppl 4 |issue= |pages=19–25 |date=January 1995 |pmid=7622819 |doi=10.1097/00004850-199501004-00003}}</ref> Side effects of moclobemide are exceptionally low,<ref name="pmid1609337">{{cite journal |author=Priest RG, Baldwin DS, Bullock T, Kibel D, Smeyatsky N, Steinert J |title=Recent advances in antidepressant drugs |journal=S. Afr. Med. J. |volume=Suppl |issue= |pages=1–4 |date=June 1992 |pmid=1609337 }}</ref> with [[insomnia]], headache and dizziness being the most commonly reported side effects in the initial stages of therapy with moclobemide.<ref name="pmid7954486">{{cite journal |author=Moll E, Neumann N, Schmid-Burgk W, Stabl M, Amrein R |title=Safety and efficacy during long-term treatment with moclobemide |journal=Clin Neuropharmacol |volume=17 Suppl 1 |issue= |pages=S74–87 |year=1994 |pmid=7954486 |doi=10.1097/00002826-199417001-00009}}</ref> Many antidepressants have an adverse effect on sexual function; however, treatment with moclobemide has actually been found to improve sexual function.<ref name="pmid8144126">{{cite journal |author=Baier D, Philipp M |title=[Modification of sexual functions by antidepressants] |language=German |journal=Fortschr Neurol Psychiatr |volume=62 |issue=1 |pages=14–21 |date=January 1994 |pmid=8144126 |doi=10.1055/s-2007-996652 }}</ref> Moclobemide does not have any adverse effect on cognitive abilities, thus there are no impairments of moclobemide therapy on memory, attention functions nor is ability to drive a motor vehicle affected adversely.<ref name="pmid8174512">{{cite journal |author=Amado-Boccara I, Gougoulis N, Poirier-Littré MF, Galinowski A, Lôo H |title=[Effects of antidepressants on cognitive functions. Review of the literature] |language=French |journal=Encephale |volume=20 |issue=1 |pages=65–77 |year=1994 |pmid=8174512 }}</ref> In fact, moclobemide has been found to improve cognition, especially memory; this is relevant with regard to the elderly as adverse effects on cognition are of particular concern in this population. People with dementia and [[comorbid]] depression also show improvements in cognitive impairments; these improvements are unrelated to alleviation of depression. Alcohol related cognitive impairments are also improved by moclobemide. Improvements in cognition also occur in young depressed people after 6 weeks of treatment. There is a mild impairment in psychometric performance in elderly people but none in younger people. Moclobemide, even at high doses of 600 mg, does not impair the ability to drive a motor vehicle.<ref name="pmid7905288"/><ref name="pmid1377119"/> The tolerability of moclobemide is similar in women and men and it is also well tolerated in the elderly.<ref name="pmid2123366">{{cite journal |author=Versiani M, Nardi AE, Figueira IL, Stabl M |title=Tolerability of moclobemide, a new reversible inhibitor of monoamine oxidase-A, compared with other antidepressants and placebo |journal=Acta Psychiatr Scand Suppl |volume=360 |issue= |pages=24–8 |year=1990 |pmid=2123366 }}</ref> Moclobemide is tolerated to a similar degree to the SSRI antidepressants, although unlike SSRIs moclobemide does not cause sexual dysfunction and gastrointestinal disturbance is less common. Moclobemide has been found to be superior to tricyclic and irreversible MAOI antidepressants in terms of side effects, as it does not cause [[anticholinergic]], sedative or cardiovascular adverse effects<ref name="pmid8875133"/> as well as not causing weight gain.<ref name="pmid1377119">{{cite journal |author=Fitton A, Faulds D, Goa KL |title=Moclobemide. A review of its pharmacological properties and therapeutic use in depressive illness |journal=Drugs |volume=43 |issue=4 |pages=561–96 |date=April 1992 |pmid=1377119 |doi=10.2165/00003495-199243040-00009}}</ref> | |||
Unlike the irreversible MAOIs there is no evidence of liver toxicity with moclobemide.<ref name="pmid1394030">{{cite journal |author=Amrein R, Hetzel W, Stabl M, Schmid-Burgk W |title=RIMA: a safe concept in the treatment of depression with moclobemide |journal=Can J Psychiatry |volume=37 Suppl 1 |issue= |pages=7–11 |date=September 1992 |pmid=1394030 }}</ref> Moclobemide has a similar efficacy profile compared to other antidepressants but is significantly superior to the tricyclic antidepressants and the classic (unselective or irreversible) MAOIs, in terms of tolerance and safety profile.<ref name="pmid7741983">{{cite journal |author=Norman TR, Burrows GD |title=A risk-benefit assessment of moclobemide in the treatment of depressive disorders |journal=Drug Saf |volume=12 |issue=1 |pages=46–54 |date=January 1995 |pmid=7741983 |doi=10.2165/00002018-199512010-00004}}</ref> Moclobemide has little effect on [[Psychomotor learning|psychomotor]] functions.<ref name="pmid2248062"/> Other side effects include, nausea, insomnia, tremor and lightheadedness; [[orthostatic hypotension]] is uncommon even among the elderly.<ref name="pmid10063483"/> Behavioural toxicity or other impairments relating to everyday living does not occur with moclobemide, except in doses of 400 mg or higher, peripheral reaction time may be impaired.<ref name="pmid1546141">{{cite journal |author=Hindmarch I, Kerr J |title=Behavioural toxicity of antidepressants with particular reference to moclobemide |journal=Psychopharmacology (Berl.) |volume=106 Suppl |issue= |pages=S49–55 |year=1992 |pmid=1546141 |doi=10.1007/bf02246236}}</ref> [[Peripheral oedema]] has been associated with moclobemide.<ref name="pmid1630391">{{cite journal |author=Alderman CP, Callary JA, Kent AL |title=Peripheral oedema associated with moclobemide |journal=Med. J. Aust. |volume=157 |issue=2 |pages=144 |date=July 1992 |pmid=1630391 }}</ref> | |||
Most of the side effects are transient disappearing within 2 weeks of treatment.<ref name="pmid7593727">{{cite journal |author=Tiller JW, Johnson GF, Burrows GD |title=Moclobemide for depression: an Australian psychiatric practice study |journal=J Clin Psychopharmacol |volume=15 |issue=4 Suppl 2 |pages=31S–34S |date=August 1995 |pmid=7593727 |doi=10.1097/00004714-199508001-00006}}</ref> [[tiredness]], headache, restlessness, nervousness and sleep disturbances have been described as side effects from moclobemide therapy.<ref name="Rimón-1993">{{Cite journal | last1 = Rimón | first1 = R. | last2 = Jääskeläinen | first2 = J. | last3 = Kaartinen | first3 = P. | last4 = Kalli | first4 = A. | last5 = Kilponen | first5 = E. | last6 = Koskinen | first6 = T. | last7 = Nikkilä | first7 = H. | last8 = Pirttiperä | first8 = V. | last9 = Seppälä | first9 = J. | title = Moclobemide versus imipramine in depressed out-patients: a double-blind multi-centre study | journal = Int Clin Psychopharmacol | volume = 7 | issue = 3–4 | pages = 141–7 |date=Jan 1993 | pmid = 8468435 | doi=10.1097/00004850-199300730-00004 }}</ref> A [[paradoxical effect|paradoxical]] worsening of depression has been reported in some individuals in several studies,<ref name="pmid8354766">{{cite journal |title=Moclobemide: a reversible MAO-A-inhibitor showing weaker antidepressant effect than clomipramine in a controlled multicenter study. Danish University Antidepressant Group |journal=J Affect Disord |volume=28 |issue=2 |pages=105–16 |date=June 1993 |pmid=8354766 |doi=10.1016/0165-0327(93)90039-M}}</ref> and reports of suicidal ideation and suicide as an adverse effect have been reported as a rare adverse effect of moclobemide.<ref name="pmid7941097">{{cite journal |author=Gram LF |title=[Antidepressive drug therapy, suicidal ideation and suicide, 2 cases reported in connection with moclobemide (Aurorix) therapy] |language=Danish |journal=Ugeskr. Laeg. |volume=156 |issue=38 |pages=5542 |date=September 1994 |pmid=7941097 }}</ref> Overall, antidepressants decrease the risk of suicide.<ref name="pmid9272192">{{cite journal |author=Isacsson G, Holmgren P, Druid H, Bergman U |title=The utilization of antidepressants--a key issue in the prevention of suicide: an analysis of 5281 suicides in Sweden during the period 1992-1994 |journal=Acta Psychiatr Scand |volume=96 |issue=2 |pages=94–100 |date=August 1997 |pmid=9272192 |doi=10.1111/j.1600-0447.1997.tb09912.x}}</ref> Moclobemide is believed to have only small proconvulsant effects;<ref name="pmid9512919">{{cite journal |author=Curran S, de Pauw K |title=Selecting an antidepressant for use in a patient with epilepsy. Safety considerations |journal=Drug Saf |volume=18 |issue=2 |pages=125–33 |date=February 1998 |pmid=9512919 |doi=10.2165/00002018-199818020-00004}}</ref> however, rarely seizures may occur.<ref name="pmid7954487">{{cite journal |author=Bisserbe JC, Lépine JP |title=Moclobemide in social phobia: a pilot open study. GRP Group. Groupe de Recherche en Psychopharmacologie |journal=Clin Neuropharmacol |volume=17 Suppl 1 |issue= |pages=S88–94 |year=1994 |pmid=7954487 |doi=10.1097/00002826-199417001-00010}}</ref> [[Hypertension]], has been reported to occur very rarely with moclobemide therapy.<ref name="pmid10063483"/> | |||
Moclobemide is relatively well tolerated. The following are the potential adverse effects and their respective incidences:<ref name=SANDOZ>{{cite web|title=PRODUCT INFORMATION MOCLOBEMIDE SANDOZ® 150mg and 300mg TABLETS|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01146-3|work=TGA eBusiness Services|publisher=Sandoz|accessdate=16 October 2013|date=6 March 2012}}</ref><ref name=AURORIX>{{cite web|title=NAME OF THE DRUG AURORIX|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04017-3|work=TGA eBusiness Services|publisher=Meda Valeant Pharma Australia Pty Limited|accessdate=16 October 2013|date=7 January 2013}}</ref> | |||
;Common (>1% incidence) adverse effects | |||
* Nausea | |||
* Dry mouth | |||
* Constipation | |||
* Diarrhoea | |||
* Insomnia | |||
* Dizziness | |||
* Anxiety | |||
* Restlessness | |||
;Uncommon/Rare (<1%) adverse effects | |||
{{div col|4}} | |||
* Difficulties falling asleep | |||
* Nightmares/dreams | |||
* Hallucinations | |||
* Memory disturbances, | |||
* Confusion | |||
* Disorientation | |||
* Delusions | |||
* Increased depression | |||
* Excitation/irritability | |||
* Hypomania | |||
* Mania | |||
* Aggressive behaviour | |||
* Apathy | |||
* Tension | |||
* Suicidal ideation | |||
* Suicidal behaviour | |||
* Migraine | |||
* Extrapyramidal effects | |||
* Tinnitus | |||
* Paraesthesia | |||
* Dysarthria | |||
* Heartburn | |||
* Gastritis | |||
* Meteorism | |||
* Indigestion | |||
* Hypertension | |||
* Bradycardia | |||
* Extrasystoles | |||
* Angina/chest pain | |||
* Phlebetic symptoms | |||
* Flushing | |||
* Exanthema/rash | |||
* Allergic skin reaction | |||
* Itching | |||
* Gingivitis | |||
* Stomatitis | |||
* Dry skin | |||
* Conjunctivitis | |||
* Pruritus | |||
* Urticaria | |||
* Disturbances of micturition (dysuria, polyuria, tenesmus) | |||
* Metrorrhagia | |||
* Prolonged menstruation | |||
* General malaise | |||
* Skeletal/muscular pain | |||
* Altered taste sensations | |||
* Hot flushes/cold sensation | |||
* Photopsia | |||
* Dyspnoea | |||
* Visual disturbances | |||
* Increased hepatic enzymes without associated clinical sequelae. | |||
{{div col end}} | |||
===Contraindications=== | |||
Avoid use in:<ref name = AMH/> | |||
* Confusional states | |||
* Bipolar disorder (although it seems less likely than imipramine to cause a manic switch<ref name = BPD/>) | |||
* [[Phaeochromocytoma]] | |||
and ''caution'' is recommended in:<ref name = BNF>{{cite isbn|9780857110848}}</ref> | |||
* Agitated/excited patients | |||
* [[Thyrotoxicosis]] | |||
===Interactions=== | |||
;Drug | |||
Moclobemide has fewer interactions than irreversible MAOIs. [[Cimetidine]], however, causes a significant rise in moclobemide levels and therefore if the combination is used, lower doses of moclobemide have been recommended.<ref name="pmid2248085">{{cite journal |author=Zimmer R, Gieschke R, Fischbach R, Gasic S |title=Interaction studies with moclobemide |journal=Acta Psychiatr Scand Suppl |volume=360 |issue= |pages=84–6 |year=1990 |pmid=2248085 }}</ref> There is little increase in the effects of alcohol when combined with moclobemide<ref name="pmid2248085"/> and, in fact, moclobemide causes a reduction in alcohol-related impairments.<ref name="pmid2248062">{{cite journal |author=Tiller JW |title=Antidepressants, alcohol and psychomotor performance |journal=Acta Psychiatr Scand Suppl |volume=360 |issue= |pages=13–7 |year=1990 |pmid=2248062 }}</ref> Moclobemide also interacts with [[pethidine|pethidine/meperidine]],<ref name="pmid1546135">{{cite journal |author=Amrein R, Güntert TW, Dingemanse J, Lorscheid T, Stabl M, Schmid-Burgk W |title=Interactions of moclobemide with concomitantly administered medication: evidence from pharmacological and clinical studies |journal=Psychopharmacology (Berl.) |volume=106 Suppl |issue= |pages=S24–31 |year=1992 |pmid=1546135 |doi=10.1007/bf02246229}}</ref> and [[dextropropoxyphene]].<ref name="pmid7741983"/> [[Ephedrine]] in combination with moclobemide increases the risk of cardiovascular adverse effects.<ref name="pmid8468439">{{cite journal |author=Dingemanse J |title=An update of recent moclobemide interaction data |journal=Int Clin Psychopharmacol |volume=7 |issue=3–4 |pages=167–80 |date=January 1993 |pmid=8468439 |doi=10.1097/00004850-199300730-00008}}</ref> Moclobemide is also likely to interact with [[warfarin]].<ref name="pmid9669190">{{cite journal |author=Duncan D, Sayal K, McConnell H, Taylor D |title=Antidepressant interactions with warfarin |journal=Int Clin Psychopharmacol |volume=13 |issue=2 |pages=87–94 |date=March 1998 |pmid=9669190 |doi=10.1097/00004850-199803000-00006}}</ref> | |||
[[Serotonin syndrome]] has been reported when moclobemide has been taken in combination with other serotonin enhancing drugs; however, due to moclobemide's reversible MAO inhibition, serotonin syndrome is significantly less likely to occur with moclobemide than with older irreversible MAOIs.<ref name = AMH>{{cite isbn|978098057909}}</ref><ref name="pmid9224903">{{cite journal |author=Hilton SE, Maradit H, Möller HJ |title=Serotonin syndrome and drug combinations: focus on MAOI and RIMA |journal=Eur Arch Psychiatry Clin Neurosci |volume=247 |issue=3 |pages=113–9 |year=1997 |pmid=9224903 |doi=10.1007/BF03033064}}</ref><ref name="pmid8255982">{{cite journal |author=Tiller JW |title=Clinical overview on moclobemide |journal=Prog. Neuropsychopharmacol. Biol. Psychiatry |volume=17 |issue=5 |pages=703–12 |date=September 1993 |pmid=8255982 |doi=10.1016/0278-5846(93)90054-V}}</ref> [[Serotonin syndrome]] has been reported when [[trazodone]] was abruptly replaced with moclobemide.<ref name="pmid16104086">{{cite journal |author=Zivanović O, Till E |title=[Serotonin syndrome--a case account] |journal=Med. Pregl. |volume=45 |issue=3–4 |pages=116–8 |year=1992 |pmid=16104086 }}</ref> Taking at the same time or starting moclobemide too soon after discontinuing [[clomipramine]], or other serotonin reuptake inhibitors, such as SSRIs may result in the development of a serotonin syndrome.<ref name="pmid7741983"/><ref name="pmid8443525">{{cite journal |author=Spigset O, Mjörndal T, Lövheim O |title=Serotonin syndrome caused by a moclobemide-clomipramine interaction |journal=BMJ |volume=306 |issue=6872 |pages=248 |date=January 1993 |pmid=8443525 |pmc=1676747 |doi=10.1136/bmj.306.6872.248}}</ref> [[SNRI]]s, such as venlafaxine in combination with moclobemide have also been associated with serotonin syndrome.<ref name="pmid9631680">{{cite journal |author=Roxanas MG, Machado JF |title=Serotonin syndrome in combined moclobemide and venlafaxine ingestion |journal=Med. J. Aust. |volume=168 |issue=10 |pages=523–4 |date=May 1998 |pmid=9631680 }}</ref> [[Cimetidine]], causes a doubling of the blood plasma levels of moclobemide.<ref name="pmid7905288"/> Blood plasma levels of [[trimipramine]] and [[maprotiline]] and possibly other tricyclic antidepressants increase when used in combination with moclobemide and may require dosage adjustments if the combination is used for treatment resistant depression.<ref name="pmid9271778">{{cite journal |author=König F, Wolfersdorf M, Löble M, Wössner S, Hauger B |title=Trimipramine and maprotiline plasma levels during combined treatment with moclobemide in therapy-resistant depression |journal=Pharmacopsychiatry |volume=30 |issue=4 |pages=125–7 |date=July 1997 |pmid=9271778 |doi=10.1055/s-2007-979497 }}</ref> The elimination of [[zolmitriptan]] is reduced by moclobemide and if the combination is used, a dosage reduction of zolmitriptan is recommended.<ref name="pmid9399014">{{cite journal |author=Rolan P |title=Potential drug interactions with the novel antimigraine compound zolmitriptan (Zomig, 311C90) |journal=Cephalalgia |volume=17 Suppl 18 |issue= |pages=21–7 |date=October 1997 |pmid=9399014 }}</ref> Moclobemide reduces the metabolism of [[dextromethorphan]].<ref name="pmid9489930">{{cite journal |author=Härtter S, Dingemanse J, Baier D, Ziegler G, Hiemke C |title=Inhibition of dextromethorphan metabolism by moclobemide |journal=Psychopharmacology (Berl.) |volume=135 |issue=1 |pages=22–6 |date=January 1998 |pmid=9489930 |doi=10.1007/s002130050481}}</ref> | |||
;Dietary | |||
Irreversible MAOIs can cause unpleasant and occasionally dangerous side effects such as a [[hypertensive crises]] after intake of food or drink containing indirectly acting sympathomimetic amines such as [[tyramine]]. This is sometimes referred to as the 'cheese effect'. These side effects are due to irreversible inhibition of MAO in the gut and vasomotor neurones. However, the reversible MAOI antidepressants such as moclobemide have a very different side effect profile in this regard.<ref name="pmid7905288"/> The reversible binding to MAO-A by moclobemide allows amines such as tyramine to displace moclobemide from MAO-A allowing its metabolism and removing the risk of a hypertensive crisis that occurs with irreversible MAO inhibition.<ref name="Lavian-1993">{{Cite journal | last1 = Lavian | first1 = G. | last2 = Finberg | first2 = JP. | last3 = Youdim | first3 = MB. | title = The advent of a new generation of monoamine oxidase inhibitor antidepressants: pharmacologic studies with moclobemide and brofaromine | journal = Clin Neuropharmacol | volume = 16 Suppl 2 | pages = S1–7 | year = 1993 | pmid = 8313392 }}</ref> Of 2300 people in multiple clinical trials who were treated with moclobemide in doses up to 600 mg with no dietary restrictions, none experienced a tyramine-mediated [[hypertensive]] reaction.<ref name="pmid2123366"/> As the pressor effect of moclobemide is so low, dietary restrictions are not necessary in people eating a normal diet, in contrast to irreversible MAOIs.<ref name="pmid8875133"/> However, some rare cheeses that have a high tyramine level may possibly cause a pressor effect and require caution.<ref name="pmid3283290">{{cite journal |author=Da Prada M, Zürcher G, Wüthrich I, Haefely WE |title=On tyramine, food, beverages and the reversible MAO inhibitor moclobemide |journal=J. Neural Transm. Suppl. |volume=26 |issue= |pages=31–56 |year=1988 |pmid=3283290 }}</ref> The potentiation of the pressor effect of tyramine by moclobemide is only one seventh to one tenth of that of irreversible MAOIs.<ref name="pmid2248084">{{cite journal |author=Zimmer R |title=Relationship between tyramine potentiation and monoamine oxidase (MAO) inhibition: comparison between moclobemide and other MAO inhibitors |journal=Acta Psychiatr Scand Suppl |volume=360 |issue= |pages=81–3 |year=1990 |pmid=2248084 }}</ref> In order to minimize this potentiation, postprandial administration (taken after meals) of moclobemide is recommended.<ref name="pmid7905288"/> The combined use of moclobemide and [[selegiline]] requires dietary restrictions as the combination can lead to increased sensitivity to the pressor effect of foods containing tyramine.<ref name="pmid9673855">{{cite journal |author=Heinonen EH, Myllylä V |title=Safety of selegiline (deprenyl) in the treatment of Parkinson's disease |journal=Drug Saf |volume=19 |issue=1 |pages=11–22 |date=July 1998 |pmid=9673855 |doi=10.2165/00002018-199819010-00002}}</ref> | |||
The combination of moclobemide with prescription or over the counter [[sympathomimetic drug]]s is not recommended due to the potential of significant drug interactions.<ref name="pmid8713690">{{cite journal |author=Livingston MG, Livingston HM |title=Monoamine oxidase inhibitors. An update on drug interactions |journal=Drug Saf |volume=14 |issue=4 |pages=219–27 |date=April 1996 |pmid=8713690 |doi=10.2165/00002018-199614040-00002}}</ref> While moclobemide or the irreversible MAO-B selective inhibitor selegiline taken alone has very little pressor effect, and requires no dietry restriction, the combination of [[seligiline]] with moclobemide leads to a significant enhancement of the pressor effect and such a combination requires dietary restriction of foods containing high amounts of [[tyramine]].<ref name="pmid8857072">{{cite journal |author=Korn A, Wagner B, Moritz E, Dingemanse J |title=Tyramine pressor sensitivity in healthy subjects during combined treatment with moclobemide and selegiline |journal=Eur. J. Clin. Pharmacol. |volume=49 |issue=4 |pages=273–8 |year=1996 |pmid=8857072 |doi=10.1007/BF00226327}}</ref> The combination of moclobemide and a reversible MAO-B inhibitor requires tyramine dietary restrictions.<ref name="pmid8861736">{{cite journal |author=Dingemanse J, Hussain Y, Korn A |title=Tyramine pharmacodynamics during combined administration of lazabemide and moclobemide |journal=Int J Clin Pharmacol Ther |volume=34 |issue=4 |pages=172–7 |date=April 1996 |pmid=8861736 }}</ref> | |||
===Overdose=== | |||
Moclobemide is considered to be less toxic in overdose compared to older antidepressants, such as the tricyclic antidepressants and nonselective, irreversible MAO inhibitors,<ref name="pmid8875133"/> making it a safer antidepressant in the elderly or people with physical disorders.<ref name="pmid1377119"/> Of 18 people who overdosed on moclobemide during clinical trials, all recovered fully and moclobemide was judged to be safe for in as well as outpatient use.<ref name="pmid1546127">{{cite journal |author=Hetzel W |title=Safety of moclobemide taken in overdose for attempted suicide |journal=Psychopharmacology (Berl.) |volume=106 Suppl |issue= |pages=S127–9 |year=1992 |pmid=1546127 |doi=10.1007/bf02246256}}</ref> Intoxications with moclobemide as single agent are usually mild; however, when combined with tricyclic or SSRI antidepressants the overdose much more toxic and potentially fatal.<ref name="pmid8433071">{{cite journal |author=Myrenfors PG, Eriksson T, Sandsted CS, Sjöberg G |title=Moclobemide overdose |journal=J. Intern. Med. |volume=233 |issue=2 |pages=113–5 |date=February 1993 |pmid=8433071 |doi=10.1111/j.1365-2796.1993.tb00662.x}}</ref><ref name="pmid7901695">{{cite journal |author=Neuvonen PJ, Pohjola-Sintonen S, Tacke U, Vuori E |title=Five fatal cases of serotonin syndrome after moclobemide-citalopram or moclobemide-clomipramine overdoses |journal=Lancet |volume=342 |issue=8884 |pages=1419 |date=December 1993 |pmid=7901695 |doi=10.1016/0140-6736(93)92774-N}}</ref> Moclobemide, is preferred by doctors for patients who are at risk of suicide, due to moclobemide's low toxicity in overdose.<ref name="pmid7819894">{{cite journal |author=Isacsson G, Redfors I, Wasserman D, Bergman U |title=Choice of antidepressants: questionnaire survey of psychiatrists and general practitioners in two areas of Sweden |journal=BMJ |volume=309 |issue=6968 |pages=1546–9 |date=December 1994 |pmid=7819894 |pmc=2541721 |doi=10.1136/bmj.309.6968.1546}}</ref> 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 and tolerance=== | |||
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 mocloemide therapy has been reported in one patient.<ref name="Curtin-2002">{{Cite journal | last1 = Curtin | first1 = F. | last2 = Berney | first2 = P. | last3 = Kaufmann | first3 = C. | title = Moclobemide discontinuation syndrome predominantly presenting with influenza-like symptoms | journal = J Psychopharmacol | volume = 16 | issue = 3 | pages = 271–2 |date=Sep 2002 | pmid = 12236637 | doi=10.1177/026988110201600314}}</ref> Withdrawal of moclobemide causes a rebound in REM Sleep.<ref name="pmid7905288"/> | |||
Moclobemide does not prevent withdrawal symptoms from [[serotonin reuptake inhibitors]].<ref name="pmid8889907">{{cite journal |author=Coupland NJ, Bell CJ, Potokar JP |title=Serotonin reuptake inhibitor withdrawal |journal=J Clin Psychopharmacol |volume=16 |issue=5 |pages=356–62 |date=October 1996 |pmid=8889907 |doi=10.1097/00004714-199610000-00003}}</ref> | |||
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.<ref name="pmid9074307"/> | |||
==Pharmacology== | ==Pharmacology== | ||
[[File:Moclobemide 150 mg tablets.jpg|thumb|A picture of 150 mg tablets of the reversible [[MAOI]] drug moclobemide, brand name Aurorix.]] | |||
Moclobemide is a [[benzamide]],<ref name="pmid10063483"/> derivative of [[morpholine]],<ref name="pmid9112832">{{cite journal |author=Ghanbarpour A, Hadizadeh F, Piri F, Rashidi-Ranjbar P |title=Synthesis, conformational analysis and antidepressant activity of moclobemide new analogues |journal=Pharm Acta Helv |volume=72 |issue=2 |pages=119–22 |date=April 1997 |pmid=9112832 |doi=10.1016/S0031-6865(97)00004-6}}</ref> which acts pharmacologically as a selective, [[reversible inhibitor of monoamine oxidase A]] (RIMA),<ref name="pmid8875133">{{cite journal |author=Fulton B, Benfield P |title=Moclobemide. An update of its pharmacological properties and therapeutic use |journal=Drugs |volume=52 |issue=3 |pages=450–74 |date=September 1996 |pmid=8875133 |doi=10.2165/00003495-199652030-00013}}</ref> a type of monoamine oxidase inhibitor (MAOI), and increases levels of [[norepinephrine]] (noradrenaline), [[dopamine]], and especially [[serotonin]].<ref name="Nair">{{cite journal | last = Nair | first = N. P. |author2=S. K. Ahmed |author3=N. M. Kin |date=November 1993 | title = Biochemistry and pharmacology of reversible inhibitors of MAO-A agents: focus on moclobemide | journal = Journal of Psychiatry & Neuroscience | volume = 18 | issue = 5 | pages = 214–225 | publisher = Canadian Psychiatric Association | location = Ontario | pmc = 1188542 | pmid=7905288 }}</ref><ref name="pmid1546143">{{cite journal |author=Haefely W, Burkard WP, Cesura AM, et al. |title=Biochemistry and pharmacology of moclobemide, a prototype RIMA |journal=Psychopharmacology (Berl.) |volume=106 Suppl |issue= |pages=S6–14 |year=1992 |pmid=1546143 |doi=10.1007/bf02246225}}</ref> 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 [[3-adrenoceptors]]. A single 300 mg dose of moclobemide inhibits 80% of monoamine oxidase A (MAO-A) and 30% of monoamine oxidase B (MAO-B), blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. There is also some evidence pointing towards moclobemide possessing [[neuroprotective]] properties.<ref name="pmid7905288"/> There is no cumulative effect of moclobemide centrally when taken long-term.<ref name="pmid7905288"/> With long-term use of moclobemide, there is a significant [[down-regulation]] of [[B-adrenoceptors]].<ref name="pmid7905288"/> Single or repeated dosing with 100–300 mg of moclobemide leads to a reduction in deaminated metabolites of [[amines]] such as [[3,4-dihydroxyphenylacetic acid]], [[3,4-dihydroxyphenylethylglycol]] as well as [[5-HIAA]]. Excretion of [[homovanillic acid]] and [[vanillylmandelic acid]] via urine is also reduced. There is also a temporary increase in [[prolactin]] during initial intake of 100–300 mg of moclobemide.<ref name="pmid7905288"/> L-dihydroxyphenylalanine is also reduced.<ref name="pmid8923574">{{cite journal |author=Radat F, Berlin I, Spreux-Varoquaux O, Elatki S, Ferreri M, Puech AJ |title=Initial monoamine oxidase-A inhibition by moclobemide does not predict the therapeutic response in patients with major depression. A double blind, randomized study |journal=Psychopharmacology (Berl.) |volume=127 |issue=4 |pages=370–6 |date=October 1996 |pmid=8923574 |doi=10.1007/bf02806017}}</ref> However, suppression of the serotonin metabolite is less pronounced than the inhibition of the metabolite of noradrenaline which suggest there are other major metabolic pathways for serotonin other than MAO-A.<ref name="pmid7519866">{{cite journal |author=Holford NH, Guentert TW, Dingemanse J, Banken L |title=Monoamine oxidase-A: pharmacodynamics in humans of moclobemide, a reversible and selective inhibitor |journal=Br J Clin Pharmacol |volume=37 |issue=5 |pages=433–9 |date=May 1994 |pmid=7519866 |pmc=1364898 |doi=10.1111/j.1365-2125.1994.tb05710.x}}</ref> | |||
== | 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.<ref name="pmid7905288"/> With three times daily dosing the inhibition on MAO-A was relatively constant with moclobemide.<ref name="pmid1546145">{{cite journal |author=Dingemanse J, Berlin I, Payan C, Thiede HM, Puech AJ |title=Comparative investigation of the effect of moclobemide and toloxatone on monoamine oxidase activity and psychometric performance in healthy subjects |journal=Psychopharmacology (Berl.) |volume=106 Suppl |issue= |pages=S68–70 |year=1992 |pmid=1546145 |doi=10.1007/bf02246239}}</ref> The MAO inhibition of moclobemide lasts about 8–10 hours and wears off completely by 24 hours after dosing.<ref name="pmid7905288"/><ref name="pmid1546143"/> The inhibition of MAO-A by moclobemide is 10 times more potent than the irreversible MAOIs [[phenelzine]] and approximately equivalent to [[tranylcypromine]] and [[isocarboxazid]].<ref name="pmid7905288"/> | ||
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Moclobemide increases levels of extracellular [[monoamines]] and decreases levels of their metabolites in rat brains; tolerance to these effects does not seem to occur with chronic use of moclobemide. Moclobemide lacks [[anticholinergic]] effects and cognitive impairments can be improved by moclobemide.<ref name="Haefely-1993">{{Cite journal | last1 = Haefely | first1 = W. | last2 = Burkard | first2 = WP. | last3 = Cesura | first3 = A. | last4 = Colzi | first4 = A. | last5 = Kettler | first5 = R. | last6 = Lorez | first6 = HP. | last7 = Martin | first7 = JR. | last8 = Moreau | first8 = JL. | last9 = Richards | first9 = JG. | last10 = Schaffner | first10 = R | title = Pharmacology of moclobemide | journal = Clin Neuropharmacol | volume = 16 Suppl 2 | issue = | pages = S8–18 | year = 1993 | doi = | pmid = 8313402 | display-authors = 8 }}</ref> Moclobemide suppresses the unstimulated release of certain [[proinflammatory cytokine]]s which are believed to be involved in the pathophysiology of major depression and stimulates the release of anti-inflammatory cytokines.<ref name="pmid10760560">{{cite journal |author=Lin A, Song C, Kenis G, et al. |title=The in vitro immunosuppressive effects of moclobemide in healthy volunteers |journal=J Affect Disord |volume=58 |issue=1 |pages=69–74 |date=April 2000 |pmid=10760560 |doi=10.1016/S0165-0327(99)00076-2}}</ref> Long-term treatment with moclobemide leads to an increase in [[cyclic adenosine monophosphate]] (cAMP) binding to [[cAMP-dependent protein kinase]] (PKA).<ref name="pmid9694007">{{cite journal |author=Mori S, Zanardi R, Popoli M, et al. |title=cAMP-dependent phosphorylation system after short and long-term administration of moclobemide |journal=J Psychiatr Res |volume=32 |issue=2 |pages=111–5 |year=1998 |pmid=9694007 |doi=10.1016/S0022-3956(98)00003-X }}</ref> | |||
Moclobemide is chemically unrelated to irreversible MAOI antidepressants and only has a very weak pressor effect of orally administered [[tyramine]].<ref name="pmid2677242">{{cite journal |author=Da Prada M, Kettler R, Keller HH, Burkard WP, Haefely WE |title=Preclinical profiles of the novel reversible MAO-A inhibitors, moclobemide and brofaromine, in comparison with irreversible MAO inhibitors |journal=J. Neural Transm. Suppl. |volume=28 |issue= |pages=5–20 |year=1989 |pmid=2677242 }}</ref> 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.<ref name="pmid7905288"/> | |||
[[ | In healthy people moclobemide has a relatively small suppressing effect on [[REM sleep]]; in contrast, depressed people who have been treated with moclobemide, progressively show improved sleep over a 4-week period, with an increase in stage 2 non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep.<ref name="pmid7905288"/> There have been conflicting findings with regard to moclobemide altering [[cortisol]] levels and whether moclobemide increases [[growth hormone]] levels.<ref name="pmid7905288"/> [[Testosterone]] levels increase significantly with long-term use of moclobemide in depressed males.<ref name="Plasma sex hormones and urinary biogenic amine metabolites during treatment of male depressed patients with the monoamine oxidase inhibitor moclobemide">{{cite journal |author=Markianos M, Alevizos V, Stefanis C |title=Plasma sex hormones and urinary biogenic amine metabolites during treatment of male depressed patients with the monoamine oxidase inhibitor moclobemide |journal=Neuro endocrinology letters |volume=13 |issue=1 |pages=49–55 |year=1991 |issn=0172-780X}}</ref> | ||
Moclobemide also has neuroprotective properties in its demonstrated anti-[[Hypoxia (medical)|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.<ref name="pmid7905288"/> Moclobemide has also been demonstrated in a single dose research study to possess [[antinociceptive]] properties.<ref name="pmid8375130">{{cite journal |author=Coquoz D, Porchet HC, Dayer P |title=Central analgesic effects of desipramine, fluvoxamine, and moclobemide after single oral dosing: a study in healthy volunteers |journal=Clin. Pharmacol. Ther. |volume=54 |issue=3 |pages=339–44 |date=September 1993 |pmid=8375130 |doi=10.1038/clpt.1993.156}}</ref> | |||
The | 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.<ref name="pmid9663810">{{cite journal |author=Bitsios P, Langley RW, Tavernor S, et al. |title=Comparison of the effects of moclobemide and selegiline on tyramine-evoked mydriasis in man |journal=Br J Clin Pharmacol |volume=45 |issue=6 |pages=551–8 |date=June 1998 |pmid=9663810 |pmc=1873648 |doi=10.1046/j.1365-2125.1998.00729.x}}</ref> 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,<ref name="pmid8259692">{{cite journal |author=Vallès B, Coassolo P, De Sousa G, Aubert C, Rahmani R |title=In vitro hepatic biotransformation of moclobemide (Ro 11-1163) in man and rat |journal=Xenobiotica |volume=23 |issue=10 |pages=1101–11 |date=October 1993 |pmid=8259692 | doi = 10.3109/00498259309059425 }}</ref> blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. No [[reuptake]] inhibition of any of the [[neurotransmitter]]s 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). | ||
As MAO inhibition returns completely back to normal after 24 hours, which allows for changing to another antidepressant within 24 hours of the last dose taken of moclobemide.<ref name="pmid7905288"/> | |||
==Pharmacokinetics== | |||
In humans moclobemide is rapidly and almost completely absorbed and totally metabolised via the liver.<ref name="pmid8582117"/> Peak plasma levels occur 0.3 to 2 hours after oral administration. The bioavailability increases during the first week of therapy from 60% to 80% and more. The elimination half-life is around 2 hours.<ref name="pmid7905288">{{cite journal |author=Nair NP, Ahmed SK, Kin NM |title=Biochemistry and pharmacology of reversible inhibitors of MAO-A agents: focus on moclobemide |journal=J Psychiatry Neurosci |volume=18 |issue=5 |pages=214–25 |date=November 1993 |pmid=7905288 |pmc=1188542 }}</ref><ref name="Lei">{{cite book|last1=Leikin |first1=Jerrold B. |last2=Paloucek |first2=Frank P. |title=Poisoning and toxicology handbook |url=http://books.google.com/?id=0Bw2UJTC_uMC |accessdate=26 May 2009 |edition=4th |year=2007 |publisher=Informa Health Care |isbn=978-1-4200-4479-9 |pages=1331 |chapter=Moclobemide | |||
|chapterurl=http://books.google.co.uk/books?id=0Bw2UJTC_uMC&pg=PA475&lpg=PA475&dq=moclobemide+half-life+elimination&source=bl&ots=W57mEtjpVx&sig=TZFCHZ9JT8mRGHPvNVrb-LiHIiQ&hl=en&ei=fRkdSpbcFY7UjAfdjviGDQ&sa=X&oi=book_result&ct=result&resnum=2#PPA475,M1}}</ref> It is moderately bound to plasma proteins, especially [[albumin]].<ref name="pmid7905288"/> However, the short [[disposition]] half life somewhat increases after repeated dosing; moclobemide has an intermediate elimination half life for [[systemic clearance]] and an intermediate [[volume of distribution]].<ref name="pmid8582117">{{cite journal |author=Mayersohn M, Guentert TW |title=Clinical pharmacokinetics of the monoamine oxidase-A inhibitor moclobemide |journal=Clin Pharmacokinet |volume=29 |issue=5 |pages=292–332 |date=November 1995 |pmid=8582117 |doi=10.2165/00003088-199529050-00002}}</ref> 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]].<ref name="Gram">{{cite journal | author=Gram L. F., Guentert T. W., Grange S., et al. |date=June 1995 | title=Moclobemide, a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6, and CYP1A2: A panel study | journal=Clinical Pharmacology & Therapeutics | volume=57 | issue=6 | pages=670–677 | publisher=American Society for Clinical Pharmacology and Therapeutics | issn=0009-9236 | doi=10.1016/0009-9236(95)90230-9 }}</ref> Less than 1 percent of the drug is excreted unchanged; 92 percent of the metabolised drug is excreted within the first 12 hours.<ref name="pmid2248086">{{cite journal |author=Jauch R, Griesser E, Oesterhelt G, et al. |title=Biotransformation of moclobemide in humans |journal=Acta Psychiatr Scand Suppl |volume=360 |issue= |pages=87–90 |year=1990 |pmid=2248086 |doi=10.1111/j.1600-0447.1990.tb05344.x}}</ref> 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;<ref name="Din">{{cite journal | author=Härtter S., Dingemanse J., Baier D., et al. |date=August 1996 | title=The role of cytochrome P450 2D6 in the metabolism of moclobemide | journal=European Neuropsychopharmacology | volume=6 | issue=3 | pages=225–230 | publisher=Elsevier Science | doi=10.1016/0924-977X(96)00023-5 | pmid=8880082 }}</ref><ref name="pmid8329293">{{cite journal |author=Gram LF, Brøsen K |title=Moclobemide treatment causes a substantial rise in the sparteine metabolic ratio. Danish University Antidepressant Group |journal=Br J Clin Pharmacol |volume=35 |issue=6 |pages=649–52 |date=June 1993 |pmid=8329293 |pmc=1381610 |doi=10.1111/j.1365-2125.1993.tb04196.x}}</ref> 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.<ref name="pmid2685852">{{cite journal |author=Schoerlin MP, Guentert TW |title=[Pharmacokinetics and metabolism of reversible MAO-A inhibitors in the human] |language=German |journal=Psychiatr Prax |volume=16 Suppl 1 |issue= |pages=11–7 |date=August 1989 |pmid=2685852 }}</ref> About 44 percent of the drug is lost due to the [[first pass effect]] through the liver.<ref name="pmid6538424">{{cite journal |author=Raaflaub J, Haefelfinger P, Trautmann KH |title=Single-dose pharmacokinetics of the MAO-inhibitor moclobemide in man |journal=Arzneimittelforschung |volume=34 |issue=1 |pages=80–2 |year=1984 |pmid=6538424 }}</ref> 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.<ref name="pmid9259175">{{cite journal |author=Goldberg RJ |title=Antidepressant use in the elderly. Current status of nefazodone, venlafaxine and moclobemide |journal=Drugs Aging |volume=11 |issue=2 |pages=119–31 |date=August 1997 |pmid=9259175 |doi=10.2165/00002512-199711020-00004}}</ref> Food slows the absorption but does not affect the bioavailability of moclobemide.<ref name="pmid7905288"/> | |||
Steady state concentrations are established after one week.<ref name="pmid8582117"/> It has been suggested that changes in dose should not be made with a gap of no less than a week.<ref name="pmid2248087">{{cite journal |author=Guentert TW, Tucker G, Korn A, Pfefen JP, Haefelfinger P, Schoerlin MP |title=Pharmacokinetics of moclobemide after single and multiple oral dosing with 150 milligrams 3 times daily for 15 days |journal=Acta Psychiatr Scand Suppl |volume=360 |issue= |pages=91–3 |year=1990 |pmid=2248087 |doi=10.1111/j.1600-0447.1990.tb05345.x}}</ref> Moclobemide has good penetration across the [[blood brain barrier]] with peak plasma levels within the central nervous system occurring 2 hours after administration.<ref name="pmid1705137">{{cite journal |author=Berlin I, Zimmer R, Thiede HM, et al. |title=Comparison of the monoamine oxidase inhibiting properties of two reversible and selective monoamine oxidase-A inhibitors moclobemide and toloxatone, and assessment of their effect on psychometric performance in healthy subjects |journal=Br J Clin Pharmacol |volume=30 |issue=6 |pages=805–16 |date=December 1990 |pmid=1705137 |pmc=1368300 |doi=10.1111/j.1365-2125.1990.tb05445.x}}</ref> | |||
==Animal toxicology== | |||
* Acute toxicity: The oral {{LD50}} values in mouse and rat are quite high, indicating a wide [[therapeutic index]]. LD<sub>50</sub> 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. | |||
==History== | ==History== | ||
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 the 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.<ref name="pmid1394027">{{cite journal |author=Roth M, Guelfi JD |title=The efficacy of reversible monoamine oxidase inhibitors in depressive illness |journal=Can J Psychiatry |volume=37 Suppl 1 |issue= |pages=18–24 |date=September 1992 |pmid=1394027 }}</ref><ref name="pmid1609042">{{cite journal |author=Rudorfer MV |title=Monoamine oxidase inhibitors: reversible and irreversible |journal=Psychopharmacol Bull |volume=28 |issue=1 |pages=45–57 |year=1992 |pmid=1609042 }}</ref> In 1992 moclobemide was launched onto the world markets.<ref name="pmid7593735">{{cite journal |author=Hilton S, Jaber B, Ruch R |title=Moclobemide safety: monitoring a newly developed product in the 1990s |journal=J Clin Psychopharmacol |volume=15 |issue=4 Suppl 2 |pages=76S–83S |date=August 1995 |pmid=7593735 |doi=10.1097/00004714-199508001-00013}}</ref> Moclobemide was the first reversible MAO-A inhibitor to be widely marketed;<ref name="pmid9005342">{{cite journal |author=Volz HP, Gleiter CH, Möller HJ |title=[Monoamine oxidase inhibitors in psychiatry. Status of current knowledge] |language=German |journal=Nervenarzt |volume=67 |issue=5 |pages=339–47 |date=May 1996 |pmid=9005342 }}</ref> Moclobemide as well as other newer antidepressants such as the SSRIs lead to changes in prescribing patterns and broadened the treatment options for the management of depressive disorders.<ref name="pmid7980156">{{cite journal |author=Mitchell PB, Mitchell MS |title=The management of depression. The place of the new antidepressants. Part 1. General overview |journal=Aust Fam Physician |volume=23 |issue=8 |pages=1555–9, 1562 |date=August 1994 |pmid=7980156 }}</ref> | |||
The discovery of moclobemide in 1972 in Switzerland,<ref name="pmid10063483"/> as an antidepressant came about after it was initially investigated as a possible lipid lowering drug or antibiotic; when tests failed to demonstrate any antibiotic or [[antilipaemic]] properties; it was then tested for anti-cholinergic properties to see if it was a possible antidepressant but these tests also proved negative, leading researchers to think it may, in fact, be an antipsychotic; finally its reversible MAO-A properties as well as its lack of tyramine pressor effect. Clinical trials were commenced for moclobemide's effectiveness in the treatment of depression.<ref name="pmid8923103">{{cite journal |author=Angst J, Amrein R, Stabl M |title=Moclobemide: a paradigm of research in clinical psychopharmacology |journal=Int Clin Psychopharmacol |volume=11 Suppl 3 |issue= |pages=3–7 |date=June 1996 |pmid=8923103 |doi=10.1097/00004850-199606003-00002}}</ref> It was first approved in the UK and Europe as the first reversible and selective inhibitor of MAO-A an is now approved in over 50 countries world wide.<ref name="pmid10063483"/> Subsequent research found that moclobemide is well tolerated in elderly patients<ref name="pmid9469236">{{cite journal |author=Amrein R, Stabl M, Henauer S, Affolter E, Jonkanski I |title=Efficacy and tolerability of moclobemide in comparison with placebo, tricyclic antidepressants, and selective serotonin reuptake inhibitors in elderly depressed patients: a clinical overview |journal=Can J Psychiatry |volume=42 |issue=10 |pages=1043–50 |date=December 1997 |pmid=9469236 }}</ref> and far superior to tricyclic antidepressants in terms of side effects/tolerability as well as being much safer in 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; because of these benefits of moclobemide over existing antidepressant drugs, moclobemide became regarded as a beneficial addition to medical 'prescribing arsenal'.<ref name="pmid8255982"/><ref name="pmid8253702">{{cite journal |author=Bech P |title=Acute therapy of depression |journal=J Clin Psychiatry |volume=54 Suppl |issue= |pages=18–27; discussion 28 |date=August 1993 |pmid=8253702 }}</ref> Additionally moclobemide was found to, unlike most other antidepressants on the market, to actually improve all aspects of sexual function.<ref name="pmid9696909">{{cite journal |author=Chebili S, Abaoub A, Mezouane B, Le Goff JF |title=[Antidepressants and sexual stimulation: the correlation] |language=French |journal=Encephale |volume=24 |issue=3 |pages=180–4 |year=1998 |pmid=9696909 }}</ref> It is the only reversible MAOI in use in clinical practice.<ref name="pmid7905288"/> The fact that moclobemide's pharmacokinetic properties are unaltered by age, that cognition is improved in the elderly, and moclobemide has low potential for food and drug interactions opened up a new avenue for the treatment of [[major depressive disorder]].<ref name="pmid7905288"/> Due to a lack of financial incentive, such as the costs of conducting the necessary trials to gain approval, moclobemide is unavailable in the USA pharmaceutical market.<ref name="pmid10063483"/> | |||
==References== | ==References== | ||
{{ | {{reflist|2}} | ||
==Further reading== | ==Further reading== | ||
* | *Scientific Information on Aurorix (German) | ||
*[http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=189524 PubChem Substance Summary: Moclobemide] National Center for Biotechnology Information. | |||
{{Antidepressants}} | |||
{{Dopaminergics}} | |||
{{Serotonergics}} | |||
[[Category: | [[Category:Reversible inhibitors of MAO-A]] | ||
[[Category: | [[Category:Monoamine oxidase inhibitors]] | ||
[[Category:Organochlorides]] | [[Category:Organochlorides]] | ||
[[Category: | [[Category:Benzamides]] | ||
[[Category: | [[Category:Morpholines]] | ||
Revision as of 17:20, 7 April 2015
File:Moclobemide.svg | |
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Clinical data | |
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Trade names | Amira, Aurorix, Clobemix, Depnil, Manerix |
AHFS/Drugs.com | Micromedex Detailed Consumer Information |
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Routes of administration | oral |
ATC code | |
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Pharmacokinetic data | |
Bioavailability | 55-95% (increases with repeat administration)[3][4] |
Protein binding | 50%[4][5] |
Metabolism | Hepatic[1][2] |
Elimination half-life | 1-2 hours,[2] 4 hours (elderly)[4][6] |
Excretion | Renal, Faecal (<5%)[5] |
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DrugBank | |
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KEGG | |
ChEBI | |
ChEMBL | |
E number | {{#property:P628}} |
ECHA InfoCard | {{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value). |
Chemical and physical data | |
Formula | C13H17ClN2O2 |
Molar mass | 268.739 g/mol |
3D model (JSmol) | |
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Moclobemide (sold as Amira, Aurorix,[7] Clobemix , Depnil and Manerix[8]) is a reversible monoamine oxidase inhibitor (MAOI) drug primarily used to treat depression and social anxiety.[9][10][11] It is not approved for use in the United States,[12] but is approved in other Western countries such as the UK[11] and Australia (TGA approved in December 2000).[13] It is produced by affiliates of the Hoffmann–La Roche pharmaceutical company. Initially, Aurorix was also marketed by Roche in South Africa, but was withdrawn after its patent rights expired and Cipla Medpro's Depnil and Pharma Dynamic's Clorix became available at half the cost.
No significant rise in blood pressure occurs when moclobemide is combined with amines such as tyramine containing foods or pressor amine drugs, unlike the older non-selective irreversible MAOIs which cause a severe rise in blood pressure with such combination.[9] Due to the lack of anticholinergic, cardiovascular, cognitive and psychomotor impairments moclobemide is advantageous in the elderly as well as those with cardiovascular disease.[9]
Medical uses
Reversible selective MAOIs such as moclobemide are widely underprescribed due to the misconception that the side effect profile of moclobemide is analogous to that of the irreversible and non-selective MAOIs.[14] MAOIs such as moclobemide are reported to have a relatively fast onset of action compared to other antidepressant drug classes,[15] and have good long-term tolerability in terms of side effects.[16]
Tolerance does not seem to occur; research has found that moclobemide retains its beneficial therapeutic properties in depression for at least a year.[17]
- Unipolar depression. Moclobemide has demonstrated effectiveness and efficacy in the treatment and management of major depressive disorder,[18] 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.[19] Due to a very good safety profile and very low incidence of side effects moclobemide is likely to have a high level of acceptability by individuals suffering from depression.[20] Higher doses (>450 mg/day) may be more effective in severe depression, while patients treated with a lower dose tend to respond less well than those treated with tricyclic antidepressants.[21]
- Psychotic depression, unipolar endogenous depression, melancholic depression, retarded depression, agitated depression and neurotic depression all respond to moclobemide.[22] As does atypical depression.[23] Unipolar endogenous depression is reported to have the best response to moclobemide therapy.[24][25] Individuals suffering from depression who are given moclobemide are twice as likely to improve on moclobemide than on placebo.[26] A concern of antidepressant adverse effects is sexual dysfunction; however, moclobemide has actually been found to increase the libido and also improve impaired erection, ejaculation and orgasm.[27] 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.[28]
- 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.[29]
- Bipolar depression. While not generally recommended as a monotherapy for bipolar depression (as with all antidepressants) in one clinical trial it appeared (although statistical significance at the p=0.05 was not reached) as though moclobemide was equally effective as imipramine at reducing depressive symptoms, but had a significantly lower risk of causing a manic switch.[30] This is in line with recent findings that MAOIs as a class are superior to other antidepressants (in terms of both their relatively low rate of manic switching and their efficacy) in the treatment of bipolar depression.[31]
- Dysthymia; moclobemide has been found to be effective in the treatment and management of this depressive disorder.[32]
- 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.[33] Moclobemide is effective but not as effective as the irreversible MAOIs in the treatment of social phobia.[34] Maximal benefits can take 8 – 12 weeks to manifest.[35] There is a high risk of treatment failure if there is co-morbid alcohol abuse, however.[36] The Australian Medicines Handbook lists social phobia as an accepted but not a licensed indication.[10]
- 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,[37] and moclobemide could therefore help increase abstinence rates due to moclobemide mimicking the MAO-A inhibiting effects of tobacco smoke. Moclobemide was administered for 3 months and then stopped; at 6 months follow-up it was found those who had taken moclobemide for 3 months had a much higher successful quit rate than those in the placebo group. However, at 12-month follow-up the difference between the placebo group and the moclobemide group was no longer significant.[38]
- Panic disorder. Moclobemide is useful in the treatment and management of panic disorder.[39] Panic disorder is mentioned as an accepted but unlicensed indication in the Australian Medicines Handbook.[10]
- ADHD. Two small studies assessing the benefit of moclobemide in people with attention deficit disorder found that moclobemide produced favourable results.[22]
- Fibromyalgia, moclobemide has been found to improve pain and functioning in this group of people.[40]
- Migraine. Moclobemide has been reported to be effective in the treament of migraine and chronic tension headache.[41][42]
Similar to other MAOIs, reversible MAOIs such as moclobemide may also be effective in a range of other psychiatric disorders.[22][43] Menopausal flushing may also respond to moclobemide.[44] Moclobemide may also have benefit for some patients with Parkinson's Disease by extending and enhancing the effects of l-dopa.[45]
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.[12] 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.[9][46] 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.[14]
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.[47][48]
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.[49]
Pregnancy and lactation
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.[8]
Children
Use in children is not recommended as there is insufficient data to assess their safety and efficacy in these patients.[10][11]
Elderly
Reversible MAOIs such as moclobemide may have advantages in the treatment of depression associated with Alzheimer's disease due to its effect on noradrenaline.[50] Cognitive impairments have been found to improve in people with dementia when depression is treated with moclobemide.[22] Due to its superior safety profile, moclobemide has been recommended as a first line agent for the treatment of depression in the elderly.[51] Due to the side effect profile of moclobemide, it may be a better option for this sub group of people than other antidepressants.[52] Research has found evidence that moclobemide may be able to counter cholinergic induced cognitive impairments thus making moclobemide a good choice in the depression in the elderly and those with dementia.[53]
Adverse effects
The incidence of adverse events is not correlated with age; however, adverse events occur more often in females than in males.[54] Moclobemide is regarded as a generally safe antidepressant and due to its favorable side effect profile, it can be considered a first-line therapeutic antidepressant.[55] Side effects of moclobemide are exceptionally low,[20] with insomnia, headache and dizziness being the most commonly reported side effects in the initial stages of therapy with moclobemide.[56] Many antidepressants have an adverse effect on sexual function; however, treatment with moclobemide has actually been found to improve sexual function.[57] Moclobemide does not have any adverse effect on cognitive abilities, thus there are no impairments of moclobemide therapy on memory, attention functions nor is ability to drive a motor vehicle affected adversely.[58] In fact, moclobemide has been found to improve cognition, especially memory; this is relevant with regard to the elderly as adverse effects on cognition are of particular concern in this population. People with dementia and comorbid depression also show improvements in cognitive impairments; these improvements are unrelated to alleviation of depression. Alcohol related cognitive impairments are also improved by moclobemide. Improvements in cognition also occur in young depressed people after 6 weeks of treatment. There is a mild impairment in psychometric performance in elderly people but none in younger people. Moclobemide, even at high doses of 600 mg, does not impair the ability to drive a motor vehicle.[8][59] The tolerability of moclobemide is similar in women and men and it is also well tolerated in the elderly.[60] Moclobemide is tolerated to a similar degree to the SSRI antidepressants, although unlike SSRIs moclobemide does not cause sexual dysfunction and gastrointestinal disturbance is less common. Moclobemide has been found to be superior to tricyclic and irreversible MAOI antidepressants in terms of side effects, as it does not cause anticholinergic, sedative or cardiovascular adverse effects[9] as well as not causing weight gain.[59]
Unlike the irreversible MAOIs there is no evidence of liver toxicity with moclobemide.[61] Moclobemide has a similar efficacy profile compared to other antidepressants but is significantly superior to the tricyclic antidepressants and the classic (unselective or irreversible) MAOIs, in terms of tolerance and safety profile.[62] Moclobemide has little effect on psychomotor functions.[63] Other side effects include, nausea, insomnia, tremor and lightheadedness; orthostatic hypotension is uncommon even among the elderly.[12] Behavioural toxicity or other impairments relating to everyday living does not occur with moclobemide, except in doses of 400 mg or higher, peripheral reaction time may be impaired.[64] Peripheral oedema has been associated with moclobemide.[65]
Most of the side effects are transient disappearing within 2 weeks of treatment.[66] tiredness, headache, restlessness, nervousness and sleep disturbances have been described as side effects from moclobemide therapy.[67] A paradoxical worsening of depression has been reported in some individuals in several studies,[68] and reports of suicidal ideation and suicide as an adverse effect have been reported as a rare adverse effect of moclobemide.[69] Overall, antidepressants decrease the risk of suicide.[70] Moclobemide is believed to have only small proconvulsant effects;[71] however, rarely seizures may occur.[72] Hypertension, has been reported to occur very rarely with moclobemide therapy.[12]
Moclobemide is relatively well tolerated. The following are the potential adverse effects and their respective incidences:[13][73]
- Common (>1% incidence) adverse effects
- Nausea
- Dry mouth
- Constipation
- Diarrhoea
- Insomnia
- Dizziness
- Anxiety
- Restlessness
- Uncommon/Rare (<1%) adverse effects
- Difficulties falling asleep
- Nightmares/dreams
- Hallucinations
- Memory disturbances,
- Confusion
- Disorientation
- Delusions
- Increased depression
- Excitation/irritability
- Hypomania
- Mania
- Aggressive behaviour
- Apathy
- Tension
- Suicidal ideation
- Suicidal behaviour
- Migraine
- Extrapyramidal effects
- Tinnitus
- Paraesthesia
- Dysarthria
- Heartburn
- Gastritis
- Meteorism
- Indigestion
- Hypertension
- Bradycardia
- Extrasystoles
- Angina/chest pain
- Phlebetic symptoms
- Flushing
- Exanthema/rash
- Allergic skin reaction
- Itching
- Gingivitis
- Stomatitis
- Dry skin
- Conjunctivitis
- Pruritus
- Urticaria
- Disturbances of micturition (dysuria, polyuria, tenesmus)
- Metrorrhagia
- Prolonged menstruation
- General malaise
- Skeletal/muscular pain
- Altered taste sensations
- Hot flushes/cold sensation
- Photopsia
- Dyspnoea
- Visual disturbances
- Increased hepatic enzymes without associated clinical sequelae.
Contraindications
Avoid use in:[10]
- Confusional states
- Bipolar disorder (although it seems less likely than imipramine to cause a manic switch[30])
- Phaeochromocytoma
and caution is recommended in:[11]
- Agitated/excited patients
- Thyrotoxicosis
Interactions
- Drug
Moclobemide has fewer interactions than irreversible MAOIs. Cimetidine, however, causes a significant rise in moclobemide levels and therefore if the combination is used, lower doses of moclobemide have been recommended.[74] There is little increase in the effects of alcohol when combined with moclobemide[74] and, in fact, moclobemide causes a reduction in alcohol-related impairments.[63] Moclobemide also interacts with pethidine/meperidine,[75] and dextropropoxyphene.[62] Ephedrine in combination with moclobemide increases the risk of cardiovascular adverse effects.[76] Moclobemide is also likely to interact with warfarin.[77]
Serotonin syndrome has been reported when moclobemide has been taken in combination with other serotonin enhancing drugs; however, due to moclobemide's reversible MAO inhibition, serotonin syndrome is significantly less likely to occur with moclobemide than with older irreversible MAOIs.[10][78][79] Serotonin syndrome has been reported when trazodone was abruptly replaced with moclobemide.[80] Taking at the same time or starting moclobemide too soon after discontinuing clomipramine, or other serotonin reuptake inhibitors, such as SSRIs may result in the development of a serotonin syndrome.[62][81] SNRIs, such as venlafaxine in combination with moclobemide have also been associated with serotonin syndrome.[82] Cimetidine, causes a doubling of the blood plasma levels of moclobemide.[8] Blood plasma levels of trimipramine and maprotiline and possibly other tricyclic antidepressants increase when used in combination with moclobemide and may require dosage adjustments if the combination is used for treatment resistant depression.[83] The elimination of zolmitriptan is reduced by moclobemide and if the combination is used, a dosage reduction of zolmitriptan is recommended.[84] Moclobemide reduces the metabolism of dextromethorphan.[85]
- Dietary
Irreversible MAOIs can cause unpleasant and occasionally dangerous side effects such as a hypertensive crises after intake of food or drink containing indirectly acting sympathomimetic amines such as tyramine. This is sometimes referred to as the 'cheese effect'. These side effects are due to irreversible inhibition of MAO in the gut and vasomotor neurones. However, the reversible MAOI antidepressants such as moclobemide have a very different side effect profile in this regard.[8] The reversible binding to MAO-A by moclobemide allows amines such as tyramine to displace moclobemide from MAO-A allowing its metabolism and removing the risk of a hypertensive crisis that occurs with irreversible MAO inhibition.[86] Of 2300 people in multiple clinical trials who were treated with moclobemide in doses up to 600 mg with no dietary restrictions, none experienced a tyramine-mediated hypertensive reaction.[60] As the pressor effect of moclobemide is so low, dietary restrictions are not necessary in people eating a normal diet, in contrast to irreversible MAOIs.[9] However, some rare cheeses that have a high tyramine level may possibly cause a pressor effect and require caution.[87] The potentiation of the pressor effect of tyramine by moclobemide is only one seventh to one tenth of that of irreversible MAOIs.[88] In order to minimize this potentiation, postprandial administration (taken after meals) of moclobemide is recommended.[8] The combined use of moclobemide and selegiline requires dietary restrictions as the combination can lead to increased sensitivity to the pressor effect of foods containing tyramine.[89]
The combination of moclobemide with prescription or over the counter sympathomimetic drugs is not recommended due to the potential of significant drug interactions.[90] While moclobemide or the irreversible MAO-B selective inhibitor selegiline taken alone has very little pressor effect, and requires no dietry restriction, the combination of seligiline with moclobemide leads to a significant enhancement of the pressor effect and such a combination requires dietary restriction of foods containing high amounts of tyramine.[91] The combination of moclobemide and a reversible MAO-B inhibitor requires tyramine dietary restrictions.[92]
Overdose
Moclobemide is considered to be less toxic in overdose compared to older antidepressants, such as the tricyclic antidepressants and nonselective, irreversible MAO inhibitors,[9] making it a safer antidepressant in the elderly or people with physical disorders.[59] Of 18 people who overdosed on moclobemide during clinical trials, all recovered fully and moclobemide was judged to be safe for in as well as outpatient use.[93] Intoxications with moclobemide as single agent are usually mild; however, when combined with tricyclic or SSRI antidepressants the overdose much more toxic and potentially fatal.[94][95] Moclobemide, is preferred by doctors for patients who are at risk of suicide, due to moclobemide's low toxicity in overdose.[96] 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 and tolerance
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 mocloemide therapy has been reported in one patient.[97] Withdrawal of moclobemide causes a rebound in REM Sleep.[8]
Moclobemide does not prevent withdrawal symptoms from serotonin reuptake inhibitors.[98]
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.[14]
Pharmacology
![](/images/d/da/Moclobemide_150_mg_tablets.jpg)
Moclobemide is a benzamide,[12] derivative of morpholine,[99] which acts pharmacologically as a selective, reversible inhibitor of monoamine oxidase A (RIMA),[9] a type of monoamine oxidase inhibitor (MAOI), and increases levels of norepinephrine (noradrenaline), dopamine, and especially serotonin.[100][101] 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 3-adrenoceptors. A single 300 mg dose of moclobemide inhibits 80% of monoamine oxidase A (MAO-A) and 30% of monoamine oxidase B (MAO-B), blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. There is also some evidence pointing towards moclobemide possessing neuroprotective properties.[8] There is no cumulative effect of moclobemide centrally when taken long-term.[8] With long-term use of moclobemide, there is a significant down-regulation of B-adrenoceptors.[8] Single or repeated dosing with 100–300 mg of moclobemide leads to a reduction in deaminated metabolites of amines such as 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethylglycol as well as 5-HIAA. Excretion of homovanillic acid and vanillylmandelic acid via urine is also reduced. There is also a temporary increase in prolactin during initial intake of 100–300 mg of moclobemide.[8] L-dihydroxyphenylalanine is also reduced.[102] However, suppression of the serotonin metabolite is less pronounced than the inhibition of the metabolite of noradrenaline which suggest there are other major metabolic pathways for serotonin other than MAO-A.[103]
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.[8] With three times daily dosing the inhibition on MAO-A was relatively constant with moclobemide.[104] The MAO inhibition of moclobemide lasts about 8–10 hours and wears off completely by 24 hours after dosing.[8][101] The inhibition of MAO-A by moclobemide is 10 times more potent than the irreversible MAOIs phenelzine and approximately equivalent to tranylcypromine and isocarboxazid.[8]
Moclobemide increases levels of extracellular monoamines and decreases levels of their metabolites in rat brains; tolerance to these effects does not seem to occur with chronic use of moclobemide. Moclobemide lacks anticholinergic effects and cognitive impairments can be improved by moclobemide.[105] 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.[106] Long-term treatment with moclobemide leads to an increase in cyclic adenosine monophosphate (cAMP) binding to cAMP-dependent protein kinase (PKA).[107]
Moclobemide is chemically unrelated to irreversible MAOI antidepressants and only has a very weak pressor effect of orally administered tyramine.[108] 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.[8]
In healthy people moclobemide has a relatively small suppressing effect on REM sleep; in contrast, depressed people who have been treated with moclobemide, progressively show improved sleep over a 4-week period, with an increase in stage 2 non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep.[8] There have been conflicting findings with regard to moclobemide altering cortisol levels and whether moclobemide increases growth hormone levels.[8] Testosterone levels increase significantly with long-term use of moclobemide in depressed males.[109]
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.[8] Moclobemide has also been demonstrated in a single dose research study to possess antinociceptive properties.[110]
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.[111] 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,[112] 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).
As MAO inhibition returns completely back to normal after 24 hours, which allows for changing to another antidepressant within 24 hours of the last dose taken of moclobemide.[8]
Pharmacokinetics
In humans moclobemide is rapidly and almost completely absorbed and totally metabolised via the liver.[113] Peak plasma levels occur 0.3 to 2 hours after oral administration. The bioavailability increases during the first week of therapy from 60% to 80% and more. The elimination half-life is around 2 hours.[8][114] It is moderately bound to plasma proteins, especially albumin.[8] However, the short disposition half life somewhat increases after repeated dosing; moclobemide has an intermediate elimination half life for systemic clearance and an intermediate volume of distribution.[113] 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.[115] Less than 1 percent of the drug is excreted unchanged; 92 percent of the metabolised drug is excreted within the first 12 hours.[116] 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;[117][118] 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.[119] About 44 percent of the drug is lost due to the first pass effect through the liver.[120] 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.[121] Food slows the absorption but does not affect the bioavailability of moclobemide.[8]
Steady state concentrations are established after one week.[113] It has been suggested that changes in dose should not be made with a gap of no less than a week.[122] Moclobemide has good penetration across the blood brain barrier with peak plasma levels within the central nervous system occurring 2 hours after administration.[123]
Animal toxicology
- Acute toxicity: The oral Template:LD50 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.
History
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 the 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.[16][124] In 1992 moclobemide was launched onto the world markets.[125] Moclobemide was the first reversible MAO-A inhibitor to be widely marketed;[126] Moclobemide as well as other newer antidepressants such as the SSRIs lead to changes in prescribing patterns and broadened the treatment options for the management of depressive disorders.[127]
The discovery of moclobemide in 1972 in Switzerland,[12] as an antidepressant came about after it was initially investigated as a possible lipid lowering drug or antibiotic; when tests failed to demonstrate any antibiotic or antilipaemic properties; it was then tested for anti-cholinergic properties to see if it was a possible antidepressant but these tests also proved negative, leading researchers to think it may, in fact, be an antipsychotic; finally its reversible MAO-A properties as well as its lack of tyramine pressor effect. Clinical trials were commenced for moclobemide's effectiveness in the treatment of depression.[128] It was first approved in the UK and Europe as the first reversible and selective inhibitor of MAO-A an is now approved in over 50 countries world wide.[12] Subsequent research found that moclobemide is well tolerated in elderly patients[129] and far superior to tricyclic antidepressants in terms of side effects/tolerability as well as being much safer in 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; because of these benefits of moclobemide over existing antidepressant drugs, moclobemide became regarded as a beneficial addition to medical 'prescribing arsenal'.[79][130] Additionally moclobemide was found to, unlike most other antidepressants on the market, to actually improve all aspects of sexual function.[131] It is the only reversible MAOI in use in clinical practice.[8] The fact that moclobemide's pharmacokinetic properties are unaltered by age, that cognition is improved in the elderly, and moclobemide has low potential for food and drug interactions opened up a new avenue for the treatment of major depressive disorder.[8] Due to a lack of financial incentive, such as the costs of conducting the necessary trials to gain approval, moclobemide is unavailable in the USA pharmaceutical market.[12]
References
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- ↑ 2.0 2.1 Guentert, TW; Tucker, G; Korn, A; Pfefen, JP; Haefelfinger, P; Schoerlin, MP (1990). "Pharmacokinetics of moclobemide after single and multiple oral dosing with 150 milligrams 3 times daily for 15 days". Acta Psychiatrica Scandinavica Supplementum. 82 (S360): 91–93. doi:10.1111/j.1600-0447.1990.tb05345.x. PMID 2248087.
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Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ Versiani M, Nardi AE, Mundim FD, Alves AB, Liebowitz MR, Amrein R (September 1992). "Pharmacotherapy of social phobia. A controlled study with moclobemide and phenelzine". Br J Psychiatry. 161 (3): 353–60. doi:10.1192/bjp.161.3.353. PMID 1393304.
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- ↑ Claman JM (June 1993). "The potential effectiveness of moclobemide, the new monoamine oxidase inhibitor, in the prophylaxis of migraine". Headache. 33 (6): 339. doi:10.1111/j.1526-4610.1993.hed3306339.x. PMID 8349478.
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- ↑ Liebowitz MR, Hollander E, Schneier F; et al. (1990). "Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders". Acta Psychiatr Scand Suppl. 360: 29–34. doi:10.1111/j.1600-0447.1990.tb05321.x. PMID 2248064.
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- ↑ Alevizos B, Hatzimanolis J, Markianos M, Stefanis CN (April 1993). "Clinical, endocrine and neurochemical effects of moclobemide in depressed patients". Acta Psychiatr Scand. 87 (4): 285–90. doi:10.1111/j.1600-0447.1993.tb03373.x. PMID 8488751.
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- ↑ De Vanna, M; Kummer, J; Agnoli, A; Gentili, P; Lorizio, A; Anand, R (1990). "Moclobemide compared with second-generation antidepressants in elderly people". Acta Psychiatr Scand Suppl. 360: 64–6. PMID 2248077.
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Further reading
- Scientific Information on Aurorix (German)
- PubChem Substance Summary: Moclobemide National Center for Biotechnology Information.
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