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Antidepressants are widely used in the general population, primarily to treat depression
but also commonly in conditions such as anxiety disorders and neuropathic pain. This
article considers the significant pharmacodynamic and pharmacokinetic drug interactions
of different antidepressants, whilst remembering that individual patient characteristics
are of utmost importance in the prescribing decision.
drugs metabolised through this enzyme.5 This varying reports or as a case series where proof of causality is
ability to metabolise certain drugs may in part explain rarely available. Where formal studies do exist they
why some patients develop adverse effects and toxicity often involve a small number of participants who are
when exposed to drug interactions while others appear fit and healthy or they use a low dose of the offending
symptom free. Other individual characteristics to con drug.6 Therefore, extrapolating this evidence base to
sider are age-related changes and comorbidities of indi complex clients with multiple comorbidities and mul
viduals, which often increase the risk and worsen the tiple medication regimens needs to be done with cau
tolerability to drug interactions. tion. For some, an emerging drug–drug interaction
The evidence base supporting drug–drug interac may actually be beneficial while for others the slightest
tions is often limited, with very few formal interaction change in drug levels or adverse-effect profiles will not
studies. Most drug interactions are detected during be tolerated or acceptable. As with all prescribing,
clinical experience and published either as single case when determining the relevance and significance of a
Sertraline Clozapine+
Unlikely to cause other clinically significant
pharmacokinetic drug interactions
*Avoid – high risk combination either due to the clinical significance or the potential toxicity of the affected drug
+ Use with caution – monitor the combination closely for any adverse effects
Foods to avoid Foods which can be eaten Mirtazapine is a noradrenergic and specific serotoner
in modest amounts gic antidepressant often used as a second-line antide
pressant when sedation and appetite stimulation are
Aged cheeses (eg Processed, cottage and
English Stilton, cream cheese, ricotta
required.2 Mirtazapine has three main metabolic path
Cheshire, Danish Blue) cheese, yogurt (including ways via CYP2D6, 1A2 and 3A4 and this suggests that the
commercially available kinetic interaction profile is low as multiple routes of
pizzas from large chains) metabolism are available should an individual pathway
be inhibited.9 Mirtazapine also has no appreciable
Dried, aged, smoked, Fresh or processed meat,
inhibitory or inducing effects itself on CYP isoen
fermented fish or fish or poultry
zymes.11 However, of the few interaction studies availa
poultry
ble cimetidine, fluvoxamine and ketoconazole have
Broad bean pods, All other fruit and been shown to markedly increase mirtazapine plasma
banana peel vegetables concentrations while carbamazepine and phenytoin
Tap and unpasteurised Canned or bottled beers (CYP3A4 inducers) reduce mirtazapine plasma concen
beers and alcohol (including wine trations.11 Mirtazapine commonly causes sedation so
and chianti) may potentiate the pharmacological effects of other
sedatives (eg alcohol, benzodiazepines and antipsychot
Marmite and Brewer’s and baker’s yeast
ics) and, in particular, next day sedation and a falls risk
sauerkraut
in the elderly should be monitored for. Weight gain is
Soya products / tofu another common adverse effect of mirtazapine, which
occasionally can be problematic when the drug is com
Table 3. Dietary restrictions with MAOIs13,14
bined with antipsychotics. Mirtazapine probably has a
desvenlafaxine)15 and desvenlafaxine is itself marketed lower risk of serotonin syndrome and bleeding risk than
in some countries for depressive disorders. Cytochrome the SSRIs although this is open to some debate.11
3A4 is also involved in venlafaxine metabolism to a
lesser extent. Venlafaxine is thought to be a weak (prob Agomelatine was first approved in Europe in 2009 and
ably not significant) CYP 2D6 inhibitor15 and is not has a novel mechanism of action with melatonergic ago
known to be an inhibitor or inducer of 1A2, 2C9 or 3A4. nist (MT1 and MT2 receptors) and 5-HT2c antagonist
Drugs that may increase venlafaxine plasma levels, pre properties. It is extensively metabolised in the liver with
dominantly via 2D6 enzyme inhibition, include diphen CYP1A2 accounting for around 90% of the biotransfor
hydramine, terbinafine, bupropion and, theoretically, mation and the remaining 10% due to 2C9 and 2C19.16
fluoxetine and paroxetine. As with other serotonergic Agomelatine is not known to induce or inhibit CYP iso
antidepressants venlafaxine has been associated with enzymes11 but it can be profoundly affected by other
the risk of serotonin syndrome when combined with drugs or substances that affect CYP1A2. For example,
similarly acting drugs and has the same risk of bleeding fluvoxamine can increase the exposure of agomelatine
as the SSRIs.11 Dose-related increases in blood pressure 60-fold (range: 12- to 412-fold).16 Ciprofloxacin and
are also commonly reported with venlafaxine, so it may oestrogens are also expected to increase agomelatine
cause or worsen hypertension and potentially reverse plasma levels. Conversely cigarette smoking (especially
the benefits of antihypertensives.15 in heavy smokers [≥15 per day]) would be expected to
reduce plasma concentrations by inducing CYP1A2.11,16
Duloxetine, another SNRI, is extensively metabolised There are few pharmacodynamic interactions with ago
by CYP1A2, as its primary route and 2D6 as a secondary melatine with the exception that it has been associated
route. It is itself considered to be a moderate inhibitor with raising liver enzymes and has the potential for
of CYP2D6 so can potentially increase the levels of hepatic injury, particularly in the first few months of
drugs mainly metabolised through this route (eg TCAs, treatment.16 Patients and prescribers are advised to
tolterodine, metoprolol, risperidone and aripipra closely monitor liver enzymes (at baseline, 3, 6, 12 and
zole).5 Cigarette smoking is associated with lower 24 weeks after initiation) and watch for any signs of liver
duloxetine plasma levels (via 1A2 induction) and flu impairment. Presumably this would also be a concern if
voxamine and paroxetine have been shown to increase co-prescribed with other medication that can potentially
duloxetine levels: for example, fluvoxamine increases cause liver impairment (eg clozapine and TCAs).7
the area under the plasma concentration/time curve
of duloxetine by 460%.5,11 Similarly to venlafaxine, Vortioxetine is a relatively recent addition to the antide
duloxetine incurs a risk of serotonin syndrome, pressant market, first authorised in Europe in Decem
increased bleeding and can increase blood pressure.11 ber 2013.17 It is described as a multimodal antidepressant
www.progressnp.com Progress in Neurology and Psychiatry May/June 2016 25
Review ❚ Antidepressant drug interactions
with a variety of serotonin-specific agonist and antago risk most clinicians would agree that the MAOIs would
nist mechanisms of action (5-HT3, 5-HT7 and 5-HT1D rank first due to the concern about a hypertensive cri
receptor antagonist, 5-HT1B partial agonist, a 5-HT1A sis with foods high in tyramine and the profound risk
agonist and inhibitor of 5-HT transporter).17,18 Vortiox of serotonin syndrome with other serotonergic agents.
etine is metabolised to its major carboxylic acid metab The TCAs are likely to rank second due to their narrow
olite via the CYP2D6 pathway with CYP3A4/5 and 2C9 therapeutic index and potential for cardiotoxicity, with
as secondary routes.17 Vortioxetine itself does not show fluvoxamine ranking third because of its profound
any induction or inhibition at cytochrome P450 isoen CYP1A2 inhibition. Following these the clinical rele
zymes but may be significantly affected by inhibitors of vance of drug interactions with the antidepressants
CYP2D6 such as bupropion, fluoxetine and paroxetine becomes low as long as a few basic pharmacological
(where increased levels would be expected).18 Other parameters are considered. Of the SSRIs, fluoxetine
3A4 inhibitors (eg ketoconazole, fluconazole, itracona and paroxetine are worthy of caution because of their
zole and clarithromycin) may be expected to increase tendency to increase plasma concentrations and
vortioxetine levels while 3A4 inducers (eg carbamaze adverse effects of drugs predominantly metabolised
pine, rifampicin and phenytoin) may be expected to through CYP2D6.
decrease vortioxetine levels. The clinical significance Mirtazapine, citalopram, escitalopram and sertraline
of the 3A4 interaction is yet to be established. Along incur lower risks of drug kinetic interactions but, similar
with many other antidepressants there is risk of seroto to most antidepressants, have pharmacodynamic con
nin syndrome when combining vortioxetine with other siderations such as the risk of serotonin syndrome and
serotonin-enhancing agents. increased bleeding (less likely with mirtazapine). In
addition, caution and potential cardiac monitoring
Reboxetine and trazodone are mainly metabolised by should be considered when using citalopram or escit
CYP3A4 so are subject to inhibitors of 3A4 (eg eryth alopram with other drugs that can prolong QT intervals.
romycin, ketoconazole and ritonivor) and inducers Of course, a simple ranking of drug-interaction risk
such as carbamazepine and St John’s Wort.9 Neither does not take into account the profound and debilitat
reboxetine nor trazodone is considered to be a CYP ing consequences of having an untreated or unrespon
inducer or inhibitor on its own5 but trazodone may sive depressive disorder. In some people, despite the
incur a risk of serotonin syndrome when combined risks, MAOIs and TCAs represent an individual’s best
with similar agents. hope for recovery, so with careful monitoring and
appropriate patient education they should still be con
St John’s Wort sidered viable treatment options.
When considering drug interactions with antidepres
sants it would be appropriate to mention the herbal Stephen Bleakley is Chief Pharmacist at Salisbury NHS
product St John’s Wort (SJW). Although there is no Foundation Trust and Director and Fellow
licensed or approved product in the UK it is widely of the College of Mental Health Pharmacy.
self-prescribed for mild-to-moderate depression. SJW
has been shown to cause some dramatic interactions Declarations of interest
mainly as a result of its ability to induce CYP3A4, 2E1, No conflicts of interest were declared.
2C9 and P-glycoproteins.19 Examples of significant
drug–SJW interactions include reducing cyclosporine References
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8. Faverin (fluvoxamine maleate): Summary of product characteristics
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POEMs
Mindfulness-based stress reduction training effective for chronic low back pain
Clinical question and CBT training included 2 hours of instruction ses
Is mindfulness-based stress reduction training use sions per week for 8 weeks and an optional 6-hour
ful in the treatment of chronic low back pain in retreat for the MBSR program only. MBSR classes
adults? included mindfulness practice (body scan, yoga, and
meditation focusing on awareness of the present
Bottom line moment). CBT training focused on education about
Both mindfulness-based stress reduction (MBSR) chronic pain, relationships between the body and
training and cognitive behavior therapy (CBT) are mind and physical reactions, sleep hygiene, practice
superior to usual care alone in reducing pain and in changing dysfunctional thoughts, and pain-coping
improving function in adults with chronic low strategies. Individuals masked to treatment group
back pain. The difference in effectiveness, if any, assignment assessed outcomes by telephone inter
between MBSR and CBT is minimal. (LOE = 1b) views using validated pain and function scoring tools.
Complete follow-up occurred for approximately 90%
Reference of participants at 52 weeks. Using intention-to-treat
Cherkin DC, Sherman KJ, Balderson BH, et al. analyses, an overall clinically meaningful improve
Effect of mindfulness-based stress reduction vs ment (a greater than or equal to 30% improvement
cognitive behavioral therapy or usual care on back from baseline in functional limitations and self-re
pain and functional limitations in adults with ported back pain) occurred significantly more often
chronic low back pain. A randomized clinical trial. in patients who received either MBSR training or
JAMA 2016;315(12):1240-1249. CBT than in patients who received usual care (60.5%
and 57.7% vs 44.1%; numbers needed to treat = 6
Study design: Randomized controlled trial (sin and 7). There were no significant differences in out
gle-blinded) Funding source: Foundation comes between the MBSR and CBT groups.
Allocation: Concealed Setting: Population-based However, the benefit of functional improvement and
pain reduction compared with usual care seen at 26
Synopsis weeks was maintained at 52 weeks for MBSR but not
MBSR training focuses on increasing awareness and CBT. The study was 80% powered to detect a pre
acceptance of moment-to-moment life experiences. determined clinically meaningful difference in the
These investigators identified adults, aged 20 to 70 MBSR and CBT groups.
years, with nonspecific low back pain persisting for at
least 3 months. Eligible patients were randomly POEM (Patient Orientated Evidence that Matters)
assigned (concealed allocation) to 1 of 3 groups: (1) editors review more than 1200 studies monthly from
over 100 medical journals, presenting only the best as
usual care consisting of a $50 stipend and recom
Daily POEMs. For more information visit:
mendation to seek whatever treatment, if any, they www.essentialevidenceplus.com
choose; (2) MBSR training; or (3) CBT. The MBSR