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Is it dangerous to combine MAOIs with stimulants? According to wikpedia, Parnate, for example, "leads to an increase in the availability of monoamines, such as serotonin, norepinephrine, and dopamine, as well as a marked increase in the availability of trace amines, such as tryptamine, octopamine, and phenethylamine." A stimulant like Vyvanse, for example releases dopamine but doesn't act significantly on serotonin. So would combining the two be dangerous?
4 Drugs that Don’t Mix with Antidepressants
Antidepressants like citalopram and sertraline can help people overcome depression. At the same time, they can have adverse reactions when mixed with other drugs. People who are prescribed medication for depression should be careful about which other substances they combine with their meds. There are many drugs that don’t mix with antidepressants. If you, or someone you know, may be battling with addiction of prescription medication or recreational drugs, contact our AspenRidge Recovery Centers in Fort Collins and Lakewood (Denver Metro) for substance abuse treatment in Colorado.
Major depressive disorder (MDD) is a common psychiatric condition that significantly impairs quality of life.1 It is a recurrent illness, averaging 2 relapses per decade. The probability of recurrence increases with the number of depressive episodes.2,3 A patient who experiences major depressive episodes alternating with euthymia has unipolar depression whereas one who experiences major depressive episodes alternating with episodes of mania or hypomania has bipolar depression.4
Despite adequate dose and duration of pharmacotherapy, many individuals with unipolar or bipolar depression do not achieve and sustain remission.5 Remission rates decrease and relapse rates increase with subsequent failed antidepressant trials.6 It is difficult to identify factors that predict treatment resistance, but one review of antidepressant studies found that patients who did not demonstrate a response within 3 weeks of medication initiation were less likely to respond after a longer duration.7
Treatment-resistant depression is commonly, but not universally, defined as lack of response after trials of ≥ 2 or more antidepressants with different mechanisms of action for sufficient duration.5 This definition will be used here as well. Other definitions have proposed stages of TRD, but these require further study to evaluate their reliability and predictive utility.8 Due to lack of consensus regarding the definition of TRD, it is not possible to determine the exact prevalence of TRD.
Patients with TRD may benefit from augmentation of their medication regimen. Augmentation with lithium has yielded conflicting results, and its efficacy with newer antidepressants is not well studied.9 Triiodothyronine, buspirone, and pindolol have demonstrated some efficacy when added to serotonin reuptake inhibitors (SRIs).10,12,13 Second-generation antipsychotic drugs, antidepressant drug combinations, omega-3 fatty acids, S-adenosyl methionine (SAMe), and L-methylfolate have demonstrated some efficacy in some studies as well.12,14 In patients with depression who have not responded to these strategies, psychostimulant augmentation may be appropriate.
Combination Therapy for Treatment-Resistant Depression: Should MAOIs Be Included?
Due to the risk of adverse effects and dietary and drug interactions, use of monoamine oxidase inhibitors (MAOIs) for the treatment of depression is fairly low. Risks can include hypertensive crisis with consumption of tyramine-rich food, and serotonin syndrome (in combination with other drugs), which is why is it recommended that MOIs not be used with another antidepressant, certain prescription medications like tramadol,meperidine, dextromethorphan, or methadone, and nonprescription drugs. Because some research has indicated benefits of MAOIs combined with another antidepressant for treatment-resistant depression (TRD), a review in Pharmacotherapy evaluated data from 18 published studies and case reports and the medical records of 29 adult patients from a large Midwestern teaching hospital on the safety and efficacy of combination therapy with MAOIs and other antidepressants or stimulants for TRD. The results are as follows:
There are few controlled, prospective studies because this combination is considered to be dangerous due to the increased risk of serotonin syndrome. It is recommended that SSRIs and SNRIs be discontinued for at least two weeks before initiating MAOI treatment, except for fluoxetine which requires five weeks. Data from the case studies were uninformative or had no positive outcomes. The authors state that the risks outweigh the benefits with this combination, especially with concomitant trazodone use.
With an open-label case study and a case series, low-dose trazodone was a safe and effective treatment option for insomnia associated with MAOI use. There is limited data on its safety and efficacy in higher doses doses used to target insomnia are generally not effective as antidepressant doses. Because the risk of serotonin syndrome increased with rising doses, the risks would likely outweigh any potential benefits.
Small studies and case studies have led to mixed findings on MAOIs plus TCAs. While some have demonstrated safety, this combination is usually less well-tolerated than either agent alone. There is evidence that the combination is no more effective than either agent alone. However, in the case studies culled from the patient medical records in this review, sustained tolerability and efficacy was observed with an MAOI + TCA. The exception to this is clomipramine, which should not be used concomitantly with an MAOI.
Only three case studies assessed buproprion and tranylcypromine but had limited positive effects. While this combination may be considered for TRD, the risk of hypertension or other adverse effects should be closely monitored.
Although stimulants are not indicated for treatment of depression, they are used as an augmentation strategy and are supported by evidence in the literature as to their safety with MAOIs. Stimulants could help to normalize blood pressure in patients experiencing hypotension due to MAOI.
MAOI + Antidepressants + Stimulants
This combination has demonstrated efficacy in case reports, although the case studies from the hospital showed mixed results. The authors warn that this should be prescribed only as a last resort, including failure of electroconvulsive therapy.
While the literature supports cautious use of combining MAOIs with other antidepressants in patients with TRD who have failed multiple treatment modalities, risks of combination treatment must be considered and addressed. The authors emphasize that close supervision, under the care of an experienced clinician in psychiatry is necessary for considering combination therapy for the management of TRD in patients not responding to monotherapy or other combinations of antidepressants.
Monoamine Oxidase Inhibitors (MAOI) – Mechanism of Action | Psychopharmacology | Clinical Application
Monoamine oxidase inhibitors (MAOIs) were the first antidepressant drugs along with imipramine to be developed for treating depression. Following WW2, large amounts of rocket fuel hydrazine were given to the pharmaceutical industry. In 1952 isoniazid derived from hydrazine was found to have anti-tubercular properties. Isoniazid was serendipitously found to have mood-elevating properties, and subsequently, numerous hydrazine and non-hydrazine structures were synthesized.
However, toxicity issues coupled with its complex and numerous interactions with other drugs and dietary amines have triggered a decline in clinical use as well as causing the discontinuation of many other MAOI derivatives. [Yáñez et al. 2012]
Due to their side effect profile, MAOIs are not considered as first or second-line therapies for depression, although they still have a place in treatment-resistant depression and other disorders such as panic disorder, social phobia, and depression with atypical features. [Thase 2012]
MECHANISM OF ACTION OF MAOIs
The monoamine oxidase (MAO) enzyme catalyses the oxidative deamination of various amine substrates, including serotonin, dopamine, and noradrenaline. [Gaweska and Fitzpatrick 2011]
Inhibition of the MAO enzyme increases the synaptic availability of these neurotransmitters, the accumulation of which is suggested to be responsible for MAOIs’ antidepressant effect.
There are two types of monoamine oxidase, MAO-A and MAO-B, both of which are bound to the mitochondrial membrane’s outer surface, where they preferentially bind amines. However, these two isoforms differ in their expression levels in different tissues. [Saura Marti et al. 1990]:
- MAO-A isoenzyme metabolises serotonin, noradrenaline and dopamine, and is distributed throughout the placenta, gut, and liver.
- MAO-B preferentially metabolises benzylamine, dopamine, and phenylethylamine and is primarily found in the brain, liver, and platelets. In the brain, MAO-B is expressed mainly in glial cells and serotonergic neurons in the raphe nucleus. MAO-B breaks down serotonin only at high concentrations.
Within the CNS, Norepinephrine and dopamine neurons contain MAO-A and MAO-B with greater MAO-A content.
Outside the CNS, MAO-A predominates with only platelets and lymphocytes having MAO-B.
CLASSIFICATION OF MAOIs
MAOIs are primarily classified on whether they are selective or non-selective and reversible or non-reversible. [Meyer, 2017]
Non-selective MAOIs inhibit MAO-A and MAO-B isoforms, whereas selegiline and rasagiline are selective inhibitors of MAO-B, and moclobemide is a reversible selective inhibitor of MAO-A (RIMA).
Irreversible and nonselective:
- Hydrazine derivatives – Isocarboxazid (Marplan) and Phenelzine (Nardil)
- Cyclopropylamine inhibitor – Tranylcypromine (Parnate)
- The irreversible inhibitors will irreversibly inactivate the MAO enzyme. Their action can only be reversed by the generation of new enzyme molecules, a process that can take days or weeks.
- When given daily over several days, cumulative inhibition up to 90% or more of the target enzyme in the brain occurs in clinical use.
- Continued drug administration ensures that newly-formed enzyme molecules are also inhibited and that the enzyme activity is maintained at a constant low level.
- The clinical importance of irreversible MAOI prescribing is that a constant high degree of enzyme inhibition can be maintained over time. However, on stopping treatment, enzyme activity will remain low even after the drug itself has been cleared from the body. [Finberg and Rabey, 2016]
Non-reversible and selective
- Selegiline (Emsam) is a selective (MAO-B) and non-reversible propargylamine MAOI. Selegiline in oral form generates low plasma levels and hence acts as a selective MAO-B inhibitor. The transdermal form generates higher plasma levels and acts as a non-selective irreversible MAOI.
- Rasagiline (Azilect) is also selective (MAO-B) and non-reversible but is approved as monotherapy or adjunct therapy to levodopa in Parkinson’s disease.
- They also exert a neuroprotective activity not related to MAO inhibition. The molecular mechanism of this neuroprotective activity involves regulation of B-cell lymphoma/leukaemia 2 (BCL2) family proteins and protein kinase-dependent signalling pathways and interactions with glyceraldehyde-3-phosphate dehydrogenase and induction of some antioxidant enzymes. [Youdim, 2006]
Reversible and selective
- Reversible Selective inhibitor of MAO-A (RIMA)
- Moclobemide is a benzamide compound approved for treating depression in Australia, Europe, and Canada but not in the US.
PHARMACOLOGICAL PROFILE - PHARMACOKINETICS AND DRUG INTERACTIONS
In general, MAOIs have high bioavailability and reach peak plasma concentrations within two to three hours. Except for moclobemide (RIMA), MAOIs bind irreversibly and cumulatively inhibits up to 90% of target receptors however, antidepressant effects are typically not observed until after 4 to 8 weeks of therapy.
MAOIs should be started at a low dose and gradually titrated up to the recommended daily dosage.
- Isocarboxazid – Starting dose of 10-20 mg/day and titration up to 30-60 mg/day
- Tranylcypromine– Starting dose of 10 mg/day and titration up to 30-60 mg/day
- Phenelzine – Starting dose of 15 mg/day and titration up to 45-90 mg/day
- Selegiline – Starting dose of 6 mg/day and titration up to 6-12 mg/day
- Moclobemide – Starting dose of 150 mg/day and titration up to 300-600 mg/day
Moclobemide is subject to substantial first-pass metabolism in the liver (short half-life) this contrasts with transdermal selegiline, which bypasses the first-pass metabolism.
Transdermal selegiline was developed to bypass impairments in the gastrointestinal tract as well as hepatic first-pass metabolism. [Robinson D 2002]
Common adverse effects of MAOIs
- MAOIs are well known to have a potent hypotensive effect, which causes dizziness in approximately 50% of patients.
- MAOIs are also known to potentiate insomnia through their downstream effects on GABA and melatonin receptors.
- Other common side effects include constipation, dry mouth, sexual dysfunction, and weight gain.
Early in treatment
Later in treatment:
- Weight gain
- Muscle pain
- Paraesthesia (pyridoxine deficiency may be causal)
- Sexual dysfunction
- Hypertensive crisis or pressor response (see below)
- Persistent hypotension
- Overstimulation (activation and nervousness).
Note: Selegiline has L-methamphetamine metabolites and can be stimulating at higher doses. Selegiline has the potential for false-positive drug screens.
Contraindications and Caution:
- History of substance use disorders
- Over-use of prescribed medications
- Cerebrovascular disease
- History of recurrent or frequent headaches
- Hepatic disease/dysfunction
- Blood dyscrasias
MAOIs are not generally recommended for pregnant or breastfeeding patients due to the lack of adequate safety data. Specialist involvement is recommended.
Drug interactions involving MAO inhibitors are frequently reported, although evidence is inconsistent and of poor quality.
Two major interactions with MAOIs are:
- Stimulant like medications (amphetamine, methylphenidate, modafinil etc.)
- NARIs (atomoxetine, reboxetine)
- Anaesthetic agents
- Catecholamine-like drugs with sympathomimetic activity (i.e. mimic stimulation of sympathetic nerves, thus activating adrenergic receptors) such as ephedrine and its stereoisomer, pseudoephedrine.
Serotonergic [Gillman 2006]
- Non-selective MAOIs have also been implicated in producing serotonin syndrome (SS) when co-prescribed with SSRIs, tricyclic antidepressants, opioids (pethidine, methadone, tramadol) or amphetamines.
- Triptan migraine medications
- Tramadol, pethidine, methadone
Note that Mirtazapine and Bupropion are not present as agents that increase the risk of SS. Mirtazapine is a serotonin antagonist (5HT2A and 5HT2C antagonist) with alpha-2 antagonist effects at higher doses. Bupropion is an NDRI.
There are case reports of the emergence of serotonin syndrome even 10 weeks after MAOI is stopped.
See switching principles later.
Other reported drug interactions include:
- Other sympathomimetic drugs that are specifically contraindicated with MAOIs include apraclonidine (a selective α-2-adrenergic agonist).
- Meperidine (an opioid analgesic) is also specifically highlighted as having the potential to trigger serious drug interactions resulting in unpredictable adverse events, including death.
- MAOIs can also interact with anti-seizure medications such as carbamazepine and zonisamide, although the mechanism of interaction is not clear.
- Although not contraindicated, beta-blockers can theoretically also interact with MAOIs resulting in hypotension and bradycardia due to exaggerated vasoconstriction (i.e. a pressor response). As such, careful coadministration is recommended when these medications are used concomitantly.
TYRAMINE PRESSOR RESPONSE
Patients who are prescribed MAOIs are advised to avoid foods rich in tyramine (e.g. aged cheeses and red wine). MAOIs inhibit the breakdown of tyramine, which can quickly develop into a hypertensive crisis characterised by severe headache, anxiety, confusion, and palpitations. [Anderson et al. 1993]
- Tyramine is an amine absent in animal protein sources of diet but is enriched after decay or fermentation.
- Tyramine oxidase is found in the intestinal mucosa and breaks down the amino acid tyrosine to tyramine, which is metabolised by MAO.
- Tyramine is mainly metabolised by MAO-A with doses up to 400 mg, causing no known side effects (during a meal, people rarely ingest > 25 mg)
- Tyramine is also a substrate for (i.e. broken down) DAT, NAT, VMAT 2 and TAAR1.
- Tyramine is taken up into the cell by Noradrenaline transporter (NAT), where it interacts with TAAR1 agonistic properties at TAAR1 results in the potent release of noradrenaline. TAAR1 has a predominantly intracellular location, in which both pre-and postsynaptic effects are possible.
- Since Tyramine is metabolised by MAO, with MAO inhibition, tyramine is not metabolised in the gut and passes into the systemic circulation and cross the blood-brain barrier, displacing noradrenaline and resulting in peripheral and CNS effects.
- Complications from this crisis include haemorrhaging, cardiac failure, pulmonary oedema, and death.
- Oral agents that produce gut MAO-A inhibition tyramine doses as low as 8-10 mg may increase systolic pressure by 30 mm/hg.
- When ingested as food, tyramine doses of <50 mg are unlikely to cause a pressor response to warrant clinical attention, although some may be sensitive to 10-25 mg. (e.g. 100 mg of tyramine would require consumption of 100gm (3.5 oz) of the highest tyramine laden cheeses. [Meyer, 2017]
- For patients prescribed non-selective MAOIs, current evidence indicates that only foodstuffs having greater than 6 mg tyramine per serving pose a significant risk these include soy sauce, air-dried sausages, sauerkraut, aged chicken liver and some cheeses. [Menkes et al., 2016]
It is important to note that the tyramine content is low due to the changes in production and hygiene regulations in modern diets.
Very few foods now contain problematically high tyramine levels, that is a result of great changes in international food production methods and hygiene regulations. Cheese is the only food that, in the past, has been associated with documented fatalities resulting from hypertension. Nowadays most cheeses are quite safe, and even ‘matured’ cheeses are usually safe in healthy-sized portions. The variability of sensitivity to tyramine between individuals, and the sometimes unpredictable amount of tyramine content in foods, means a little knowledge and care are still required. [Gillman, 2016]
Of note, the transdermal delivery of selegiline allows for more targeted inhibition of MAO in the brain with minimal effect on MAO-A enzymes in the gut and hepatic systems, thus reducing its interaction with food-derived tyramine.
RANZCP clinical practice guidelines suggest that irreversible MAOIs have a third-line role in the acute treatment of depressive disorders, with particular utility for
The response rates of tranylcypromine in treatment-resistant depression have ranged from 29% to 75% in two open-label and four double-blind studies, with a median rate of 50%. [Menkes et al., 2016]
In a chart review of such patients, there was evidence that non-selective MAOIs were effective in 56% of patients who had not responded to at least three prior trials of antidepressants and in 12% who had not responded to four. [Amsterdam, 2005]
In the STAR*D study, tranylcypromine was compared with mirtazapine combined with venlafaxine in patients who had not responded to citalopram over 12–14 weeks and two further antidepressant trials. Whilst remission rates did not significantly differ [6.9% for tranylcypromine vs 13.7% for mirtazapine plus venlafaxine]. [McGrath et al., 2006]
The average dose of tranylcypromine (37 mg/day) in the STAR*D was likely to have been suboptimal despite this, those receiving the MAOI had almost twice the discontinuation rate (41%) due to adverse effects. [Menkes et al., 2016]
Problems with tolerability rather than efficacy would thus tend to relegate tranylcypromine to a third-line choice in treatment-resistant depression.
A study of people with treatment-resistant depression found that use of MAOIs while an in-patient was independently associated with both remission at the point of discharge after controlling for other treatments, particularly for unipolar treatment-resistant depression, and with being in full remission at the time of final follow-up. [Fekadu et al., 2015]
MAOIs may be used in Bipolar depression, but the evidence base is weak. MAOIs may be of particular advantage, as they appear to produce a lower manic ‘switch’ rate than TCAs and SSRIs. [Menkes et al., 2016]
The MAOI phenelzine has been studied the most, and the literature supports its ability to reduce intrusive symptoms associated with PTSD. [Kosten et al 1991] [Stein et al 2006]
However, not all MAOIs have shown efficacy, and these agents are not considered first-line. Also, it is unknown whether this effect is independent of its efficacy in reducing the symptoms of depression.
In addition, selective MAO-B inhibitors have shown efficacy in the symptomatic treatment of mild Parkinson disease during the early stages. [Ives et al. 2004]
This includes reductions in motor symptoms and a reduced requirement for levodopa without any safety concerns observed.
SSRI TO MAOI –
A washout period of 2-3 weeks is always advised after stopping an MAOI before commencing an alternative AD. (includes switching from one MAOI to another)
AUGMENTATION OPTIONS FOR PATIENTS TAKING MAOIs
- Lithium augmentation
- Second generation APs (SGAs) except Ziprasidone
- Thyroid hormone augmentation
- Successful treatment of MDD and comorbid ADHD using transdermal selegiline and lisdexamfetamine. [Israel, 2015]
- High dose Selegiline (60 mg /day) [Fiedorowicz & Swartz, 2004]
- RIMA and SSRI [Fiedorowicz & Swartz, 2004]
- Irreversible MAOIs with TCAs (safety data is limited) [Fiedorowicz & Swartz, 2004]
The MAOIs were the first antidepressants to be developed however, continued reports on their substantial side effects resulted in these drugs being quickly replaced by safer and more effective options.
Data collected from European tertiary treatment centres indicated that MAOIs were used as the primary treatment in just 0.3% of the patients with unipolar depression. [Dold et al., 2016]
The reasons for low prescribing rates of MAOIs include:
- Safety concerns
- The relative complexity of prescribing them
- Lack of sufficient clinician training [Shulman, Herrmann and Walker, 2013]
- Potential problems in the continuity of drug supplies.
Today there is a renewed interest in the pharmacology of MAOIs, particularly in patients who show a lack of response to more modern antidepressants.
Clinicians should familiarise themselves with the psychopharmacology of MAOIs and re-consider them as a valid option in treating psychiatric disorders.
New Review of TCP 2
A once in fifty-year event! A new two-part review (1, 2) of the pharmacology & efficacy of tranylcypromine! ‘Tranylcypromine in mind’.
What is more the full-text is currently freely available here
I cannot describe how pleased I am to see this: it is thorough, authoritative and timely. It adds considerably to my MAOI review (3) which is now a few years old, and my recent editorial (4). It also adds to the ground-swell of information and opinion testifying to the tremendous untapped therapeutic potential of this drug. You might well ask, ‘how can a drug that has been on the market for fifty years possibly have untapped potential’.
The simple answer is, in part: the accidents of history — it reminds me of a story recently, here in Australia, of fossickers going over an old mine site and finding a half-kilo nugget of gold.
I will add a precis of these two TCP papers soon.
Also note a couple of other recent relevant additions to the literature.
Abstracts of recent papers of interest
Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression (5)
Treatment-resistant depression (TRD) is a major health concern. More than 40% of patients treated for major depressive disorder with an appropriate antidepressant dose for an adequate duration fail to respond. Further, approximately half of adults with major depressive disorder fail to achieve sustained remission despite various medication trials. The utilization of monoamine oxidase inhibitors (MAOIs) for the treatment of depression in clinical practice today is low due to their widely known adverse effects, some of which may be life threatening, and the risk for dietary and drug interactions. For these reasons, MAOIs are not recommended to be prescribed along with other antidepressants or certain prescription or nonprescription drugs. Pharmacologic options are limited for individuals with TRD, however, and there is a paucity of data on the efficacy of MAOIs in combination with other antidepressants for the management of TRD. We performed a search of the PubMed database (inception through January 25, 2015) to identify cases that illustrate the potential utility, as well as risks, of combination treatment with MAOIs and other antidepressants for the management of TRD 18 articles met the criteria for our search. In addition, we performed a retrospective and my recent editorial (4), case series by reviewing the medical records of 29 adults treated for depression with an MAOI plus another psychotropic agent (an antidepressant or stimulant medication) between 2003 and 2012 at a large Midwestern teaching hospital. We compared the findings of the published experience with our local experience to allow for more informed decisions regarding pharmacotherapy in patients with TRD. We separated the local experience into two groups: 15 cases with the selective MAO type B inhibitor selegiline combined with medications presumed to increase the risk of serotonin syndrome and 14 cases with nonselective MAOIs (phenelzine and tranylcypromine) combined with other contraindicated medications. Although risks of combination treatment certainly exist with selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, or clomipramine, the current literature supports cautious use of combining MAOIs with other antidepressants in patients with TRD who have failed multiple treatment modalities. In addition, the data from the 29 patients receiving combination therapy with an MAOI and another antidepressant or stimulant medication revealed that 21% improved significantly, with no complications. This case series and literature review suggest that when used under close supervision and under the care of an experienced clinician in psychiatry, combination therapy may be a consideration for the management of TRD in patients not responding to monotherapy or other combinations of antidepressants.
Efficacy of Tranylcypromine in Bipolar Depression: A Systematic Review (6)
OBJECTIVE: Currently, there is a paucity of treatment options with limited efficacy for bipolar depression. The monoamine oxidase inhibitor tranylcypromine might be an effective form of treatment. The current systematic review reassesses the efficacy and safety of tranylcypromine in bipolar depression. METHODS: For this systematic review comparing tranylcypromine with placebo or active comparators in bipolar depression, relevant randomized controlled trials were identified from systematic searches of PubMed, EMBASE, and Cochrane library databases. A manual search of the references of the included studies was also performed. RESULTS: Four studies with a total of 145 participants were identified. Response rates were higher in patients treated with tranylcypromine (60.0%-80.7% overall response rate, 73.7%) compared with placebo, imipramine, and lamotrigine (the latter as add-on to a mood stabilizer) (12.9%-47.6% overall response rate, 27.5%). The overall switch rate was 6.3% for patients treated with tranylcypromine and 18.4% for patients in the control group. CONCLUSIONS: This systematic review provides evidence for the efficacy and safety of tranylcypromine treatment in bipolar depression. Additional research is required to establish the efficacy of tranylcypromine as add-on to a mood stabilizer.
Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Abeta(1-42)-induced toxicity (7).
Monoamine oxidase (MAO) enzymes play a central role in the pathogenesis of Alzheimer’s disease (AD) and MAO inhibitors (MAOIs) are antidepressant drugs currently studied for their neuroprotective properties in neurodegenerative disorders. In the present work MAOIs such as tranylcypromine [trans-(+)-2-phenylcyclopropanamine, TCP] and its amide derivatives, TCP butyramide (TCP-But) and TCP acetamide (TCP-Ac), were tested for their ability to protect cortical neurons challenged with synthetic amyloid-beta (Abeta)-(1-42) oligomers (100 nM) for 48 h. TCP significantly prevented Abeta-induced neuronal death in a concentration-dependent fashion and was maximally protective only at 10 microM. TCP-But was maximally protective in mixed neuronal cultures at 1 microM, a lower concentration compared to TCP, whereas the new derivative, TCP-Ac, was more efficacious than TCP and TCP-But and significantly protected cortical neurons against Abeta toxicity at nanomolar concentrations (100 nM). Experiments carried out with the Thioflavin-T (Th-T) fluorescence assay for fibril formation showed that TCP and its amide derivatives influenced the early events of the Abeta aggregation process in a concentration-dependent manner. TCP-Ac was more effective than TCP-But and TCP in slowing down the Abeta(1-42) aggregates formation through a lengthening at the lag phase. In our experimental model co-incubation of Abeta(1-42) oligomers with TCP-Ac was able to almost completely prevent Abeta-induced neurodegeneration. These results suggest that inhibition of Abeta oligomer-mediated aggregation significantly contributes to the overall neuroprotective activity of TCP-Ac and also raise the possibility that TCP, and in particular the new compound TCP-Ac, might represent new pharmacological tools to yield neuroprotection in AD.
MAOIs-does the evidence warrant their resurrection? (8)
Objective: The place of monoamine oxidase inhibitors (MAOIs) in psychiatry is reviewed, and the question posed as to whether they are now justifiably disregarded by prescribers. Method: Multiple databases (PubMed, Medline, Embase, Cochrane) were interrogated to provide an overview regarding the use, efficacy and toxicity of MAOIs. Data regarding funded use of these agents in New Zealand were obtained from PHARMAC. Results: Evidence supports the use of MAOIs in major depressive disorder, certain anxiety disorders and, to lesser extent, bipolar depression. Older non-selective agents, such as phenelzine and tranylcypromine, have distinctive efficacy in ‘atypical’ and treatment-resistant depression, but at the cost of serious tolerability problems. Their relegation and perception by clinicians as ‘last resort’ medications – if considered at all – has occurred in the context of various concerns, notably dietary restrictions, potential adverse drug interactions and the usual requirement for divided doses. Conclusions: Sufficient evidence supports consideration of MAOIs in treatment-refractory and atypical depressive disorders, and in social anxiety disorder. Psychiatrists in training need to gain experience in using these agents.
Use of monoamine oxidase inhibitors in chronic neurodegeneration (9)
Introduction: Neurotransmission by biogenic monoamines is important for brain function. Biogenic amine turnover employs the enzymes catechol-O-methyltransferase and monoamine oxidase in neuronal and glial cells. Inhibition of these enzymes elevates biogenic amine levels in the synaptic cleft. Subtype selectivity of inhibition is lost during long-term use of ‘selective’ monoamine oxidase inhibitors. Areas covered: This narrative review discusses use of monoamine oxidase inhibitors in the context with chronic neurodegeneration. Expert opinion: Antidepressant drugs increase synaptic concentrations of biogenic amines. In the aging brain, then one of the two enzymes involved in degrading synaptic amines, catechol-O-methyl transferase, increasingly catalyzes methylation processes. Therefore, metabolism by monoamine oxidase plays an incremental, predominant role in biogenic amine turnover, leading to greater oxidative stress. In patients with chronic neurodegenerative disorders, symptoms, such as depression and apathy, are often treated with drugs that elevate biogenic amine levels. This therapeutic strategy increases biogenic amine turnover, thereby generating neurotoxic aldehydes and enhanced oxidative stress, each of which influence and accelerate the course of neurodegeneration. We propose that antidepressant therapy should be initiated first with monoamine oxidase inhibitors only. If adequate clinical response is not achieved, only then they should be supplemented with a further antidepressant.
1. Ricken, R, Ulrich, S, Schlattmann, P, and Adli, M, Tranylcypromine in mind (Part II): Review of clinical pharmacology and meta-analysis of controlled studies in depression. Eur. Neuropsychopharmacol., 2017.
2. Ulrich, S, Ricken, R, and Adli, M, Tranylcypromine in mind (Part I): Review of pharmacology. Eur. Neuropsychopharmacol., 2017.
3. Gillman, PK, Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors. J Clin Psychopharmacol, 2011. 31(1): p. 66-74.
4. Gillman, PK, “Much ado about nothing”: Monoamine oxidase inhibitors, drug interactions and dietary tyramine. CNS Spectr, 2017: p. http://dx.doi.org/10.1017/S1092852916000651.
5. Thomas, SJ, Shin, M, McInnis, MG, and Bostwick, JR, Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression. Pharmacotherapy, 2015. 35(4): p. 433-49.
6. Heijnen, WT, De Fruyt, J, Wierdsma, AI, Sienaert, P, et al., Efficacy of Tranylcypromine in Bipolar Depression: A Systematic Review. J Clin Psychopharmacol, 2015. 35(6): p. 700-5.
7. Caraci, F, Pappalardo, G, Basile, L, Giuffrida, A, et al., Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Abeta(1-42)-induced toxicity. Eur J Pharmacol, 2015. 764: p. 256-63.
8. Menkes, D, Bosanac, P, and Castle, D, MAOIs-does the evidence warrant their resurrection? Australasian psychiatry: bulletin of Royal Australian and New Zealand College of Psychiatrists, 2016.
9. Riederer, P and Müller, T, Use of monoamine oxidase inhibitors in chronic neurodegeneration. Expert opinion on drug metabolism & toxicology, 2017. 13(2): p. 233-240.
Safety concerns with MAOIs
Consider these issues and discuss them with your doctor before taking an MAOI :
- Antidepressants and pregnancy. Some antidepressants may harm your child if you take them during pregnancy or while breast-feeding. If you're considering getting pregnant, talk to your doctor or mental health provider about the possible dangers of certain antidepressants. Don't stop taking your medication without contacting your doctor first.
- Food and beverage interactions. MAOIs can cause dangerous interactions with certain foods and beverages. You'll need to avoid foods containing high levels of tyramine ― an amino acid that regulates blood pressure ― such as aged cheeses, sauerkraut, cured meats, draft beer and fermented soy products (for example, soy sauce, miso and tofu). The interaction of tyramine with MAOIs can cause dangerously high blood pressure. Ask your doctor for a complete list of dietary restrictions, including alcohol restrictions.
- Drug interactions. MAOIs can cause serious reactions when you take them with certain medications, such as other antidepressants, certain pain drugs, certain cold and allergy medications, and some herbal supplements. Always check with your doctor or pharmacist before taking any other prescription or over-the-counter medication, herbs or other supplements while you're taking an MAOI .
- Serotonin syndrome. Rarely, an MAOI can cause dangerously high levels of serotonin, known as serotonin syndrome. It most often occurs when two medications that raise serotonin are combined. These include, for example, other antidepressants, certain pain or headache medications, and the herbal supplement St. John's wort.
- Signs and symptoms of serotonin syndrome include anxiety, agitation, high fever, sweating, confusion, tremors, restlessness, lack of coordination, major changes in blood pressure, and rapid heart rate. Seek immediate medical attention if you have any of these signs or symptoms.
Low Risk & Synergy - These drugs work together to cause an effect greater than the sum of its parts, and they aren't likely to cause an adverse or undesirable reaction when used carefully. Additional research should always be done before combining drugs.
Low Risk & No Synergy - Effects are just additive. The combination is unlikely to cause any adverse or undesirable reaction beyond those that might ordinarily be expected from these drugs.
Caution - These combinations are not usually physically harmful, but may produce undesirable effects, such as physical discomfort or overstimulation. Extreme use may cause physical health issues. Synergistic effects may be unpredictable. Care should be taken when choosing to use this combination.
Unsafe - There is considerable risk of physical harm when taking these combinations, they should be avoided where possible.
Dangerous - These combinations are considered extremely harmful and should always be avoided. Reactions to these drugs taken in combination are highly unpredictable and have a potential to cause death.
Combining medications could offer better results for ADHD patients
Three studies to be published in the August 2016 issue of the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) report that combining two standard medications could lead to greater clinical improvements for children with attention-deficit/hyperactivity disorder (ADHD) than either ADHD therapy alone.
At present, studies show that the use of several ADHD medications result in significant reductions in ADHD symptoms. However, so far there is no conclusive evidence that these standard drug treatments also improve long-term academic, social, and clinical outcomes. Research suggests that both the severity of ADHD symptoms and the degree of cognitive dysfunction that remain despite treatment contribute to poorer outcomes. As a result, more effective treatments need to be identified. One method for identifying more effective treatments is by including objective measures of the effect of ADHD treatments on brain function, which most clinical studies do not do. Using objective biological markers (or biomarkers) of patients' response to ADHD treatments could substantially advance knowledge of the neural mechanisms underlying treatment effects, helping researchers understand why there are differences in individual response.
By recruiting a sample of children and adolescents 7-14 years of age with and without ADHD, a group of researchers led by Drs. James McCracken, Sandra Loo, and Robert Bilder of the UCLA Semel Institute performed three interlocking studies examining the effects of combining standard medications on clinical, cognitive, and brain activity measures. Combined treatment was hypothesized to be superior to the two standard medications, d-methylphenidate and guanfacine, on both clinical and cognitive outcomes, and was expected to show a distinct profile of effects on brain wave activity (EEG). Participants with ADHD were randomly assigned to eight weeks of double-blinded treatment with either d-methylphenidate, guanfacine, or a combination of the two.
Clinical results showed consistent added benefits for the combined therapy over the two single treatments, especially for symptoms of inattention, and more global response indices. The rate of good clinical response went up from 62-63% in the single drug therapy to 75% in the combined therapy.
The authors argue that the modest but consistently better treatment effects of the combined treatment may have long-term significance, as less severe symptoms may lead to better outcomes. Cognitive functioning showed a slightly different pattern. Working memory improved with both combination and stimulant treatment showing roughly equal positive effects. Guanfacine, however, showed no change in working memory function despite improvement in ADHD symptomatology. Finally, the EEG study showed that only the combination therapy resulted in improved brain activity patterns that were associated with reduced ADHD symptoms and improved cognitive functions. Taken together, the results from the three studies suggest that combination therapy resulted in the best outcomes across several different domains of function, including ADHD symptom change, working memory performance, and brain activity patterns.
"ADHD is the most commonly diagnosed neuropsychiatric disorder in children, and we know full well the risks it poses for children's future success in every area of functioning. Our current treatments clearly benefit most children in the short-term, but we've yet to find ways to protect those with ADHD from suffering many of the long-term risks," McCracken said. "While we are encouraged by some of the advantages we observed of the combined treatment, we have a long way to go still in improving interventions for ADHD, as seen by the more limited cognitive effects."
"These data highlight the importance of considering cognition as a major outcome," said Bilder. "In the future, we may be able to utilize multiple objective methods such as cognitive testing and EEG to individually optimize treatments, but more work is needed, including long-term studies of treatments with proven clinical and cognitive benefits." Dr. Loo added, "The use of objective biological measures in diagnosis and treatment can also help to reduce stigma, increase acceptance of the disorder, and more accurately track treatment response to yield better outcomes."
Based on these findings, the authors conclude that combining stimulants with medications like guanfacine warrants more consideration even in children with ADHD who benefit from monotherapies. Combination treatment, with appropriate monitoring, was equally well tolerated and safe in this and prior studies. Greater consideration of the cognitive effects of treatments is necessary to improve clinical outcomes. Moreover, other treatment strategies that may yield more robust benefits are needed. As technology advances, the authors hope that more objective measures of response can make their way into routine practice. Even with such improvements, the source of individual differences in ADHD treatment response remain largely unknown. Additional long-term research on the benefits of combination treatments in large samples is necessary to confirm these findings and to further advance clinical care. If validated, combined treatments of these or potentially other compounds have the potential to dramatically improve the lives of many individuals with ADHD.
Important Drug Interactions with the SSRIs
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used psychotropic medications to treat depression and anxiety. It is important to be aware of common drug interactions between them and other medications, especially because some SSRIs are competitive inhibitors of a variety of cytochrome P450 liver enzymes. Therefore, they can significantly increase the blood levels of medications that are metabolized by those liver enzymes.
Currently, six types of SSRIs are available for prescribing in the U.S.: fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and citalopram (Celexa), escitalopram (Lexapro). These drugs are subject to extensive oxidative metabolism in the liver. Because these antidepressants have a wide therapeutic index, inhibition or induction of their metabolism is unlikely to be of concern. However, SSRIs may cause a clinically relevant inhibition of CYP enzymes, and care must be exercised when an SSRI is being added to a multidrug regimen.
The potency of the SSRIs as inhibitors of the metabolism of the P450-P2-D6 varies and is reported in descending order of potency as paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine. Fluoxetine and paroxetine are more likely to cause P450 drug interactions than citalopram and sertraline, particularly in combination with medications metabolized by or inhibiting the cytochrome P450 2D6 isoenzyme (e.g., certain antidepressants, phenothiazines,antipsychotics type IC antiarrhythmics).
Drug interactions with clinical consequences usually involve combinations of an SSRI with other psychotropics, especially monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants. The interaction between MAOIs and SSRIs is the most important drug interaction limiting SSRI use. MAOI’s are infrequently prescribed due to other options available and the high risk of interaction with other drugs.
Sertraline, citalopram and escitalopram have the lowest potential for drug interactions among the SSRIs, and are to be preferred in patients on other drugs for general medical conditions or if consideration is given to adding an SSRI to other psychotropic medication.
With the drug interaction between fluoxetine and paroxetine and codeine-based pain medications, patients can experience reduced pain relief because the CYP2D6 inhibition will reduce conversion of codeine and related medications to the clinically effective metabolite (morphine, hydromorphone, oxymorphone).
It is also important to be aware of the risk of serotonin syndrome (increase heart rate, sweating, myoclonus, hyperthermia, and agitation) when combining certain medications with SSRIs because it can be life threatening. MAOIs are contraindicated with SSRIs for this and other reasons (the combination can also increase the risk of hypertensive crisis). Be cautious when combining SSRIs with Tramodol, Meperidine, St. John’s Wort (an herbal supplement used for mild depression) or dextromethorphan.
Some studies suggest that NSAIDs can reduce the efficacy of SSRI medications, although the overall data is inconclusive. This combination may lead to increased gastrointestinal side effects.
It is our hope that this discussion is helpful for providers in the primary care setting as they are prescribing SSRIs in conjuction with other medications for their patients.