Canadian Network For Mood and Anxiety TR
Canadian Network For Mood and Anxiety TR
Canadian Network For Mood and Anxiety TR
Research report
a r t i c l e i n f o a b s t r a c t
Article history: Background: In 2001, the Canadian Psychiatric Association and the Canadian Network for Mood
Received 1 May 2009
and Anxiety Treatments (CANMAT) partnered to produce evidence-based clinical guidelines for
Accepted 23 June 2009
Available online 11 August 2009
the treatment of depressive disorders. A revision of these guidelines was undertaken by CANMAT
in 2008–2009 to reflect advances in the field.
Methods: The CANMAT guidelines are based on a question–answer format to enhance accessibility
Keywords:
to clinicians. An evidence-based format was used with updated systematic reviews of the literature
Depressive disorders
MDD and recommendations were graded according to Level of Evidence using pre-defined criteria. Lines
Antidepressant of Treatment were identified based on criteria that included Levels of Evidence and expert clinical
Pharmacotherapy support. This section on “Pharmacotherapy” is one of 5 guideline articles.
Canadian Results: Despite emerging data on efficacy and tolerability differences amongst newer
Guidelines antidepressants, variability in patient response precludes identification of specific first
Systematic review choice medications for all patients. All second-generation antidepressants have Level 1
Treatment evidence to support efficacy and tolerability and most are considered first-line treatments for
Adverse effects
MDD. First-generation tricyclic and monoamine oxidase inhibitor antidepressants are not the
Treatment-resistant depression
focus of these guidelines but generally are considered second- or third-line treatments. For
inadequate or incomplete response, there is Level 1 evidence for switching strategies and for add-
on strategies including lithium and atypical antipsychotics.
Limitations: Most of the evidence is based on trials for registration and may not reflect real-world
effectiveness.
Conclusions: Second-generation antidepressants are safe, effective and well tolerated treatments
for MDD in adults. Evidence-based switching and add-on strategies can be used to optimize
response in MDD that is inadequately responsive to monotherapy.
© 2009 Published by Elsevier B.V.
Recommendations
Differentiating and selecting antidepressants
• A thorough diagnostic assessment should be conducted, paying specific
attention to suicidality, bipolarity, comorbidity, concomitant medications,
3.1. What are the principles of pharmacotherapy management? and special features (psychosis, atypical features, seasonality).
• When clinically indicated, a laboratory assessment should be performed,
General principles of treatment with pharmacotherapy are including liver function tests and a metabolic workup.
• The use of antidepressants should be accompanied by clinical management,
similar to those for other treatment modalities for depression
including patient education, attention to adherence issues, and self-
(Patten et al., 2009). Table 2 summarizes these principles, as management techniques.
adapted for pharmacotherapy. Adherence deserves special • Patients should be carefully monitored every 1–2 weeks at the onset of
attention because early discontinuation rates of antidepressants pharmacotherapy, as this is the period of greatest risk. Depending on severity
and response, follow up can then be decreased to visits every 2–4 weeks or
are high. Although clinical practice guidelines recommend that
longer.
the minimum duration of antidepressant treatment for MDD • Monitoring should include the routine use of validated outcome scales.
should be 6–12 months, about 30% of patients discontinue • The selection of an antidepressant should be individualized based on
medications within 30 days and more than 40% discontinue clinical factors including symptom profile, comorbidity, tolerability profile,
within 90 days (Olfson et al., 2006). The main reasons cited for previous response, potential drug–drug interactions, patient preference,
and cost.
early discontinuation are lack of response, stigma associated with
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effect, course of response, common and serious adverse events, Antidepressant [brand name(s)] Mechanism Dose range
and the need to continue medications even when feeling better.
First-line recommendations
• Agomelatine⁎ [Valdoxan] MT1 and MT2 agonist; 25–50 mg
3.2. What are first-line antidepressants? 5-HT2 antagonist
a
• Bupropion [Wellbutrin] NDRI 150–300 mg
• Citalopram [Celexa, Cipramil] SSRI 20–60 mg
The previous guidelines (Kennedy et al., 2001) noted that the
• Desvenlafaxine [Pristiq] SNRI 50–100 mg
selective serotonin reuptake inhibitors (SSRIs), serotonin and • Duloxetine [Cymbalta] SNRI 60–120 mg
noradrenaline reuptake inhibitors (SNRIs), and newer agents • Escitalopram [Cipralex, ASRI 10–20 mg
were first-line medications because they have better safety and Lexapro]
tolerability profiles than older medications like tricyclic anti- • Fluoxetine [Prozac] SSRI 20–80 mg
• Fluvoxamine [Luvox] SSRI 100–300 mg
depressants (TCAs) and monoamine oxidase (MAO) inhibitors.
• Mianserin⁎ [Tolvon] α2-adrenergic agonist; 60–120 mg
This remains true, and hence this revision focuses on the 5-HT2 antagonist
comparative use of these first-line antidepressants. • Milnacipran⁎ [Ixel] SNRI 100–200 mg
Three major systematic reports published since 2001 did not • Mirtazapine [Remeron] b α2-adrenergic agonist; 30–60 mg
5-HT2 antagonist
find unequivocal efficacy or tolerability differences among the
• Moclobemide [Manerix] Reversible inhibitor of 300–600 mg
various second-generation antidepressants, all of which have MAO-A
Level 1 evidence to support efficacy (Gartlehner et al., 2007; • Paroxetine [Paxil] c
SSRI 20–60 mg
National Institute for Clinical Excellence, 2004; Sartorius et al., 25–50 mg for
2007). In addition, there are no identified consistent predictors CR version
• Reboxetine⁎ [Edronax] Noradrenaline reuptake 8–12 mg
of outcome. Therefore, most of the second-generation anti-
inhibitor
depressants can be considered first-line medications for MDD • Sertraline [Zoloft] SSRI 50–200 mg
(Table 3). • Tianeptine⁎ [Stablon, Coaxil] Serotonin reuptake 25–50 mg
TCAs are recommended as second-line antidepressants enhancer
• Venlafaxine [Effexor] d SNRI 75–375 mg
because of tolerability and safety issues and MAO inhibitors
are recommended as third-line because of tolerability and Second-line recommendations
safety issues and dietary and drug restrictions. Trazodone is • Amitriptyline, clomipramine TCA Various
also considered a second-line antidepressant because it is and others
very sedating at therapeutic doses. The selective MAO-B • Quetiapine [Seroquel] d Atypical antipsychotic 150–300 mg
• Selegiline transdermal⁎ Irreversible MAO-B 6–12 mg daily
inhibitor, selegiline transdermal, has a better tolerability
[Emsam] inhibitor transdermal
profile than the older MAO inhibitors, but because both • Trazodone [Desyrel] Serotonin reuptake 150–300 mg
dietary (at doses higher than 6 mg) and drug restrictions are inhibitor; 5-HT2 antagonist
required, it is recommended as a second-line antidepressant.
Third-line recommendations
Although the evidence for these guidelines is limited to
• Phenelzine [Nardil] Irreversible MAO inhibitors 45–90 mg
published reports, there are numerous published abstracts of • Tranylcypromine [Parnate] 30–60 mg
RCTs demonstrating efficacy of the atypical antipsychotic,
5-HT= 5-hydroxytryptamine (serotonin); ASRI = allosteric serotonin reuptake
quetiapine XR, as monotherapy for unipolar, non-psychotic
inhibitor; MAO = monoamine oxidase; MT= melatonin; NDRI = noradrenaline
MDD (e.g., (Datto et al., 2008; Cutler et al., 2009). Given the and dopamine reuptake inhibitor; SNRI = serotonin and noradrenaline
strength of this Level 1 evidence, quetiapine is included as an reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA =
efficacious antidepressant. However, given its tolerability tricyclic antidepressant.
⁎ Not available in Canada.
profile and relative lack of comparative data with SSRIs and a
Available as sustained release (SR) and extended release (XL) versions.
newer agents, quetiapine XR is recommended as a second- b
Available as rapid dissolving (RD) version.
line antidepressant. c
Available as controlled release (CR) version.
d
In general terms, the choice of first-line medication still Available as extended release (XR) version.
depends on individual assessment and matching of clinical
factors including tolerability, patient preference, and cost.
However, subsequent sections will describe the evidence for
small but clinically relevant differences among the agents in dosing, sample sizes, inclusion/exclusion criteria, duration of
efficacy, tolerability and other factors that may affect this trials, and clinically meaningful outcomes (Lieberman et al.,
decision (see Table 9 for summary). 2005). Comparisons of efficacy should specify the comparator
drugs; superiority against an individual drug should not be
3.3. What is the comparative efficacy among the SSRIs and assumed to hold true against other drugs in the same class.
newer agents? Recent meta-analyses have not shown evidence for sub-
stantive differences among classical agents (TCAs, MAOIs) and
Most RCTs are designed to evaluate efficacy against placebo SSRIs. Some meta-analyses have shown small differences in
and thus are not powered to detect smaller, but still clinically efficacy between newer antidepressants (e.g., venlafaxine over
important differences between two active agents. Meta- SSRIs [Nemeroff et al., 2008]; escitalopram over comparators
analyses can provide some comparative information but are [Kennedy et al., 2009a]) while others have not (National Institute
not substitutes for high-quality RCTs. Important factors that for Clinical Excellence, 2004; Gartlehner et al., 2007). One re-
must be weighed in comparative efficacy studies include search group has been systematically conducting comparative
R.W. Lam et al. / Journal of Affective Disorders 117 (2009) S26–S43 S29
meta-analyses for individual agents, and concluded that and newer antidepressants (Gunnell et al., 2005). In one age-
only sertraline had evidence for superior efficacy in some stratified analysis, the young adult group (18–24 years)
outcomes compared to other antidepressants (Cipriani et al., showed a small trend for increased suicidality (as per the
2008). However, these meta-analyses combined all studies at paediatric data) which did not reach statistical significance,
all doses and severity ranges. A multiple comparisons net- while in older age groups there was a trend for a protective
work meta-analysis (in which both direct and indirect effect. Nonetheless, the black box warning was extended to
comparisons are analyzed) compared 12 second-generation include the young adult group (Friedman and Leon, 2007).
antidepressants and identified a small superiority in response Naturalistic prescription and research databases have found
rates for escitalopram, mirtazapine, sertraline and venlafaxine no support for increased suicidality with antidepressant use
compared to the others (Cipriani et al., 2009). Reboxetine in adults. Similarly, the forensic database and pharmacoepi-
was the only antidepressant in the network meta-analysis demiology studies do not show any evidence for an increase
to show a significantly lower response rate than the other in suicide associated with antidepressants (Lam and Kennedy,
agents. 2004; Moller, 2006). Systematic reviews of observational
Other attempts to define superiority using RCT evidence studies have also showed reduced risk and protective effects
and pre-defined criteria have also shown some differences of SSRIs on suicide attempts and completions in adults
among the newer antidepressants. An international expert (Barbui et al., 2009).
consensus panel reviewed the head-to-head RCTs of anti- In summary, there is no clear indication that SSRIs and
depressants and concluded that clomipramine, escitalopram newer antidepressants are associated with emergent suicid-
and venlafaxine had definite evidence (defined as two or ality in young or older adults. The situation in children and
more good quality RCTs and supportive meta-analyses) of adolescents is less clear and is discussed in Question 3.21.
superiority while duloxetine, milnacipran and mirtazapine
had probable evidence (at least 2 RCTs and/or supportive 3.5. What are other serious adverse effects of antidepressants?
meta-analysis) against SSRI comparators (most commonly,
fluoxetine) (Montgomery et al., 2007). Table 4 summarizes Several uncommon but serious adverse effects of antide-
the antidepressants with at least probable evidence for pressants have been reported during long term use of
superior efficacy. antidepressants. Serotonin syndrome or neuroleptic malignant
syndrome-like events have occurred rarely when SSRIs/SNRIs
3.4. Are antidepressants associated with emergent suicidality? are co-prescribed with MAO inhibitors or other serotonergic
agents. Recent meta-analyses suggest that SSRIs are associated
The past few years have seen considerable public and with increased risk of upper gastrointestinal tract bleeding,
professional concern about emergent suicidality (defined as especially in combination with nonsteroidal anti-inflammatory
worsening or emergent suicidal ideas and attempts) asso- drugs (NSAIDs) (Loke et al., 2008) and with osteoporosis and
ciated with the newer antidepressants, leading to the “black fractures in the elderly (Takkouche et al., 2007). Hyponatremia
box warnings” in Canada, the U.S. and elsewhere. This has and agranulocytosis are also reported in a small but measurable
been chronicled in many reviews (e.g., Moller et al., 2008). percentage of patients (Mago et al., 2008). Risk estimates for
While placebo-controlled RCTs are the best way to evaluate seizures associated with antidepressants vary according to the
any emergent adverse event, the limitations of the RCT evidence sample population (Montgomery, 2005). The risk for seizures
base (spontaneous reports, lack of power to detect rare with SSRIs and the newer agents is similar to the risk in the
occurrences, exclusion of actively suicidal patients) preclude a general population (approximately 0.0–0.4%), although TCAs at
definitive conclusion (Lam and Kennedy, 2004; Moller, 2006). therapeutic doses have higher risk (0.4–1.2%). The seizure rate
The results from RCTs must be supplemented by data from associated with bupropion is dose-dependent but does not
other sources, including naturalistic treatment studies (e.g., exceed the risk with other second-generation agents when
using pharmacy and administrative databases), forensic studies prescribed within the recommended dose range. In overdose,
(e.g., toxicology studies of people who die by suicide) and venlafaxine was found to have significantly greater cardiotoxi-
pharmacoepidemiology studies. city than SSRI agents (Deshauer, 2007).
To summarize the evidence in adults, meta-analyses of
RCTs have not shown any increased risk of completed suicide 3.6. What are the differences in tolerability across antidepressants?
(Hammad et al., 2006b) or increased suicidality with SSRIs
Side effects, also known as treatment-emergent adverse
events, affect tolerability and adherence to treatment.
Commonly encountered side effects associated with the use
Table 4 of antidepressants depend primarily upon the class of
First-line antidepressants with evidence for superior efficacy against antidepressant agent chosen. In terms of overall tolerability,
comparators. meta-analyses have shown that fluvoxamine has poorer
tolerability compared to other SSRIs (Anderson, 2001) while
Antidepressant Comparators
escitalopram and sertraline have better acceptability, based
Duloxetine [Level 2] Paroxetine; pooled SSRIs
Escitalopram [Level 1] Citalopram; duloxetine; paroxetine; pooled SSRIs on overall withdrawal rates, compared to other antidepres-
Milnacipran [Level 2] Fluvoxamine; pooled SSRIs sants (Cipriani et al., 2009).
Mirtazapine [Level 2] Trazodone Meta-analyses have also identified some differences in
Sertraline [Level 1] Fluoxetine; pooled SSRIs individual side effects among the antidepressants (Brambilla
Venlafaxine [Level 1] Duloxetine; fluoxetine; pooled SSRIs
et al., 2005; Gartlehner et al., 2008). For example, within the
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SSRI class, fluoxetine has higher rates of gastrointestinal (GI) Other adverse events associated with antidepressant use
side effects including nausea, vomiting and diarrhea, fluvox- include alterations in heart rate, systolic and diastolic blood
amine has higher rates of nausea, paroxetine has more pressure (higher rates are associated with agents that block
sweating and sedation, and sertraline has higher rates of noradrenaline reuptake), and elevation of liver enzymes, but
diarrhea. Duloxetine and venlafaxine have higher rates of these effects are usually not clinically relevant. Discontinua-
nausea and vomiting than SSRIs. Mirtazapine and paroxetine tion (withdrawal) symptoms are associated with abrupt
have higher rates of weight gain, while mirtazapine and cessation, dose reduction, or tapering of some antidepres-
trazodone have higher rates of sedation. sants, especially paroxetine and venlafaxine (Baldwin et al.,
Meta-analyses, however, may not adequately differentiate 2007; Schatzberg et al., 2006).
side effect profiles among antidepressants. Other methods can
be used to compare relative side effects across individual agents. 3.7. What are the differences in treatment-emergent sexual
For example, Table 5 summarizes the unadjusted frequency of dysfunction?
adverse events as reported in product monographs. While these
rates are not adjusted for placebo and cannot take into account Although symptoms of MDD include reduced libido and
differences among the various studies, it does allow for a sexual dysfunction, many antidepressants also disturb sexual
standard reporting format. function across various domains (i.e., desire, arousal, erectile
When patients achieve a response or remission on an ability, orgasm and ejaculation). The rate of treatment-
antidepressant but continue to have troublesome side effects, emergent sexual dysfunction in RCTs is markedly under-
it may be appropriate to manage the side effects so that they estimated because of spontaneous reporting; studies using
can stay on the medication. A number of strategies have been more systematic assessment of sexual function report rates up
suggested to manage side effects, although few of these have to 50% with SSRIs and slightly lower rates with SNRIs (Taylor
been subject to controlled studies (Anderson et al., 2008). The et al., 2005). Evidence suggests that the frequency of sexual
potential benefits of using adjunctive medications to treat dysfunction within the SSRIs may be greater for fluoxetine and
side effects must be weighed against the risk of increasing the paroxetine, and lower for citalopram/escitalopram (Table 6).
side effect burden. Agomelatine, bupropion, mirtazapine, moclobemide, and sele-
Several reviews have highlighted the main differences in side giline transdermal exhibit placebo-level rates of sexual
effect profiles across classes and agents (Anderson et al., 2008; dysfunction.
Gartlehner et al., 2008; Hansen et al., 2005; Sartorius et al., There is usually little or no spontaneous remission of
2007). To summarize, the rate of GI side effects, such as nausea antidepressant-induced sexual dysfunction and there is only a
and diarrhea, associated with SSRIs/SNRIs is higher than with limited evidence base for management strategies (Taylor et al.,
antidepressants which do not primarily inhibit the serotonin 2005). Dose reduction, if possible, is sometimes beneficial. Many
reuptake transporter (e.g., agomelatine, bupropion, mirtaza- pharmacological antidotes have been proposed but relatively
pine, moclobemide). The incidence of nausea with extended few have demonstrated efficacy. Adjunctive bupropion and
release formulations (e.g., paroxetine-CR, venlafaxine-XR) is sildenafil (for antidepressant-induced erectile dysfunction)
lower when compared to the immediate release preparations. have the best evidence (Taylor et al., 2005); combination
Treatment-emergent nausea is usually most severe in the first treatment with mirtazapine is also sometimes beneficial. Many
two weeks of therapy with tolerance developing thereafter. patients will require a switch to another antidepressant with
Symptomatic treatment of GI side effects can be helpful during less propensity for sexual dysfunction (Table 6).
this time. Co-administration with food, once daily dosing at
night, and use of gastric motility agents may also reduce nausea. 3.8. What are the differences in potential for drug–drug
Central nervous system (CNS) side effects including interactions?
headaches, insomnia, sedation, nervousness and tremor also
commonly occur with antidepressants. Headaches often The concurrent use of several medications (polyphar-
respond to symptomatic treatment. Many antidepressants macy) is common in patients with MDD owing to the long
cause or worsen insomnia, although several are sleep course of depressive illness and antidepressant treatment,
promoting (e.g., agomelatine, mirtazapine, trazodone). Con- high prevalence of medical comorbidities and limited
versely, some sleep-promoting antidepressants (mirtazapine, response to antidepressant monotherapy. Therefore, drug
trazodone) are associated with high rates of daytime interactions with antidepressants are an important clinical
somnolence. Short term use of benzodiazepine or non- issue. Although fatal drug interactions are rare, clinically
benzodiazepine hypnotics (e.g., eszopiclone, zopiclone, zol- significant increases in side effects and loss of efficacy can
pidem) in carefully selected patients may improve both sleep result from antidepressant drug interactions (Preskorn et al.,
and depression outcomes (Fava et al., 2006). The judicious 2006). However, there is only a limited evidence base about
short term use of benzodiazepines also may reduce the these drug interactions (Nieuwstraten et al., 2006).
nervousness and activation associated with the initiation of Most of the drug interactions with antidepressants involve
SSRI/SNRI antidepressants. the cytochrome P450 (CYP) enzyme metabolic pathway
Metabolic adverse events include appetite stimulation, (Ereshefsky et al., 2005) or p-glycoprotein, a membrane
weight gain, disturbances in the lipid milieu and glucose transporter (Weiss et al., 2003). Since most first-line anti-
homeostasis (McIntyre et al., 2006). Most short term and depressants are metabolized through several CYP pathways,
maintenance studies suggest that SSRIs and newer agents are there are usually no significant interactions with other drugs
generally “weight neutral”, but mirtazapine and paroxetine are that act as CYP inhibitors or inducers. Rifampicin induces
associated with weight gain during longer term treatment. several CYP isoenzyme pathways (2C9, 2C19, 2D6) responsible
Table 5
Unadjusted a frequency of common adverse events as reported in product monographs of some second-generation antidepressants.
Drowsiness, Insomnia Headache Tremor Dry Blurred Sweating Delayed Dizziness/ Hypertension Tachycardia, GI pain/ Nausea Vomiting Diarrhea Constipation Nervousness/ Fatigue/ Dermatitis,
sedation, mouth vision micturition orthostatic palpitation distress anxiety aesthenia rash
somnolence hypotension
Controlled release formulations are not listed—frequency of adverse events may be lower for those formulations.
A = 9% or lower, B = 10–29%, C = 30–49%, D = 50% or higher.
⁎ = Lower than the threshold rate for reporting in monograph (usually 5% or less).
a
Some rates may be equal to, or less than, those reported for placebo.
b
At the time of publication, product monographs were not available for these agents—an updated table is available at www.canmat.org.
S31
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Table 6 Table 7
Frequency of treatment-emergent sexual dysfunction, using best available Some clinically significant drug interactions resulting from inhibition of
evidence, with first-line antidepressants. cytochrome P450 (CYP) isoenzymes.
infections, is also a reversible, non-selective MAO inhibitor differ between men and women in comparisons of venlafaxine
(Sola et al., 2006); therefore, it carries the same drug and SSRIs (Entsuah et al., 2001), of bupropion and SSRIs
restrictions as the other MAO inhibitors and should not be (Papakostas et al., 2007a), and in response to duloxetine
co-administered with antidepressants. (Kornstein et al., 2006).
Other antidepressant drug interactions are less common. With regards to severity of symptoms, several antidepres-
The combined use of serotonergic antidepressants with other sants show significant superiority against placebo in severely
serotonin enhancing drugs may result in serotonin syndrome depressed subgroups using pooled analyses of RCTs, including
(Boyer and Shannon, 2005). The bleeding risk with SSRIs agomelatine, duloxetine, escitalopram, paroxetine-CR and ven-
increases with concomitant use of anticoagulants (e.g., lafaxine. However, only escitalopram has been studied in RCTs
aspirin, warfarin) and NSAIDs (Loke et al., 2008). involving patients with higher depression severity at baseline; it
was found to be superior to fluoxetine and paroxetine
3.9. What other factors influence selection of antidepressant? (Montgomery et al., 2007).
There are conflicting results about genetic polymorphisms
Patient factors and therapeutic factors should be considered and antidepressant response. Patients carrying the short allele of
in the selection of an antidepressant (Table 9). Historically, the serotonin transporter gene appear to be more vulnerable to
antidepressant selection had been influenced by subtype of depression following adverse life events and in European studies
depression (e.g., with atypical, melancholic, or psychotic had a worse response to SSRIs (Seretti et al., 2007; Kato et al.,
features, or with seasonal pattern). However, there is limited 2008). However, variations in the gene that encodes for the
evidence to support differences in outcome among first-line 5HT2A receptor was most predictive of response to citalopram in
antidepressants for MDD with atypical or melancholic features. the STAR*D database, the largest pharmacogenetic study so far
In contrast, there is Level 1 evidence to recommend an reported (McMahon et al., 2006). Despite some promising
antidepressant combined with an antipsychotic agent for results, there is still insufficient evidence to consider routine use
MDD with psychotic features (Dannon et al., 2006), although of biomarkers to guide antidepressant selection (Table 10).
a Cochrane systematic review concluded that the combination
was superior to antipsychotic monotherapy but not to anti- Managing non-response or incomplete response
depressant monotherapy (Wijkstra et al., 2006). Given that the
latter comparison was based on only 2 RCTs, the combination 3.10. How long do you wait for a clinical response?
treatment is still recommended, unless there are specific
reasons to avoid antipsychotics. In the treatment of seasonal Most clinical trials define “clinical response” as ≥50%
MDD, there is Level 1 evidence for bupropion for prevention of reduction in the score on a depression rating scale and “clinical
winter depressive episodes (Modell et al., 2005). remission” as a score within the “normal range” of the scale.
Comorbid anxiety and substance use disorders are Clinical lore states that the lag time for antidepressant therapeutic
frequently associated with MDD, although there is also effects may be 2–4 weeks or longer. However, recent studies have
substantial overlap with eating disorders and attention deficit shown an earlier onset of action, especially in those patients who
hyperactivity disorder. While these comorbidities do not eventually respond. Several recent meta-analyses concluded that
substantially alter treatment selection, in general, there are onset of antidepressant effect can occur within 1–2 weeks of
lower rates of response and remission in patients with initiation (Papakostas et al., 2006; Posternak and Zimmerman,
comorbid conditions (Howland et al., 2009).
There is some evidence that younger adults may respond
preferentially to serotonergic rather than noradrenergic anti-
depressants, while older populations show no differential
Table 10
response (Mulder et al., 2003). The evidence for differential Summary recommendations for pharmacotherapy.
response to antidepressants between men and women is
inconsistent. In the STAR*D study, women had higher remission Recommendations
rates to citalopram than men (Young et al., 2008), while some • Appropriate assessment and monitoring of suicide risk is an important part
meta-analyses found conflicting results in remission rates of the management of MDD, however, concerns about antidepressant-
induced suicidality should not discourage initiation of treatment in adults.
between men and women (Grigoriadis et al., 2007; Khan et al.,
[Level 1]
2005). Other meta-analyses found that response rates did not • The side-effect profile of individual antidepressants should be considered
when choosing between specific medications. [Level 2]
• Uncommon but serious adverse events should be taken into consideration
when choosing an antidepressant medication for patients at elevated risk
of those events. [Level 2]
Table 9 • For patients at risk of drug–drug interactions, the effects of specific
Clinical factors that influence antidepressant selection. antidepressants on CYP isoenzymes and p-glycoprotein should be
considered when choosing an antidepressant. [Level 3]
Patient factors Therapeutic factors • Sexual side effects and metabolic indices should be monitored in patients
• Age and sex • Efficacy/tolerability/safety being treated with antidepressants. [Level 2]
• Severity • Real world effectiveness • If side effects remain troublesome in circumstances of response or remission,
• Diagnostic subtype • Potential for drug–drug interactions strategies for managing those side effects, including dose reduction,
• Comorbid disorders • Simplicity of use pharmacological antidotes and switching options, should be considered.
• Past response • Discontinuation syndrome [Level 3]
• Sensitivity to side effects • Cost • For MDD with psychotic features, antidepressants should be combined with
• Potential of biomarkers • Branded vs. generic formulation an antipsychotic medication. [Level 1]
S34 R.W. Lam et al. / Journal of Affective Disorders 117 (2009) S26–S43
3.11. What do you do when a patient does not respond? • Switch to an agent with • Amitriptyline [Level 2]
evidence for superiority, but • Clomipramine [Level 2]
Achieving and sustaining symptomatic remission is an with side effect limitations • MAO Inhibitors [Level 2]
essential first step toward functional recovery, but naturalistic
• Third-line • Add-on another agent • Buspirone [Level 2]
treatment studies show that up to 2/3 of patients will not
• Modafinil [Level 2]
experience full remission with the first antidepressant • Stimulants [Level 3]
(Trivedi et al., 2006b). When there has been no improvement • Ziprasidone [Level 3]
following an optimized (i.e., increased) dose of an antide-
pressant, the first step should be to re-evaluate diagnostic
issues (e.g., bipolarity, depressive subtype, comorbidity
including substance abuse) and treatment issues (e.g.,
adherence, side effects, suicidality). Using validated rating 3.12. How effective is the strategy of switching to a different
scales to measure response and side effects can help in the antidepressant?
clinical decision-making process (Trivedi et al., 2007).
Most of the studies examining pharmacological strategies “Switching” has been investigated in many open studies
for limited response have focused on treatment-resistant and several RCTs. Open label studies have reported good
depression (TRD). While there is no consensus definition of response and remission rates when switching for both non-
TRD, the one most commonly used is failure (i.e., lack of response and intolerability reasons. Intuitively, it seems
improvement, or b20% reduction in depression scores) reasonable to switch to an agent with a different mechanism
following adequate trials of two or more antidepressants. of action, but several RCTs and meta-analyses have shown no
The evidence base is limited by this definition, since it does differences in outcomes when switching within a class (i.e.,
not account for previous trials of augmentation/combination from one SSRI to another) compared to out of class (i.e., from
strategies or situations where there is some improvement an SSRI to a non-SSRI agent). For example, in the STAR*D
(but not to remission) with an antidepressant. effectiveness trial, there were no differences in response or
Treatment options for TRD include adding an evidence- remission rates when non-remitters to citalopram were
based psychotherapy (Parikh et al., 2009), switching to a switched to another SSRI (sertraline) or to non-SSRI agents
neurostimulation treatment such as electroconvulsive ther- (bupropion-SR or venlafaxine-XR) (Rush et al., 2006).
apy or transcranial magnetic stimulation (Kennedy et al., Similarly, a meta-analysis of 8 RCTs also found no overall
2009c), and continuing with pharmacological strategies. differences in outcomes with the type of switch after initial
Pharmacological strategies include switching to a different failure of an SSRI, although a subanalysis of 3 RCTs found a
antidepressant monotherapy, or adding another agent to the superior response when switching to venlafaxine compared
first antidepressant (Table 11; Fig. 1). The term “augmenta- to another SSRI (Ruhe et al., 2006). In contrast, another meta-
tion” has been used to describe adding a medication analysis of 4 RCTs found a small but significant effect in
that is not considered an antidepressant (e.g., lithium or remission rates, but no difference in response rates, when
thyroid hormone), while “combination” refers to adding a switching to a non-SSRI compared to another SSRI (Papakos-
second antidepressant to the first. While the evidence for tas et al., 2008).
these strategies is initially presented using these terms, Overall, there is no conclusive evidence to support switching
henceforth we will refer to them as “add-on” treatments out of class over switching within the class, for SSRI non-
because of blurring of these definitions. For example, some responders. The small differences in outcome reported in some
medications that were previously considered as augmenta- switching studies may simply be a result of enhanced efficacy of
tion agents (e.g., quetiapine) may be effective antidepressants some antidepressants, regardless of mechanism of action (see
in monotherapy. Table 4).
R.W. Lam et al. / Journal of Affective Disorders 117 (2009) S26–S43 S35
Fig. 1. Algorithm for managing limited improvement with a first-line antidepressant. 1) Initial improvement (defined as ≥20% reduction in symptom score) to a
first-line antidepressant should be apparent within 1–4 weeks of achieving a therapeutic dose. If there is not at least an initial improvement within this time frame,
and the drug is well tolerated, the dose should be increased. If there is still limited improvement, there should be a reassessment of diagnosis (especially
comorbidity), degree of improvement (such as number and type of residual symptoms), adherence and tolerability. 2) At any step, depending on severity and
patient preference, adding an evidence-based, non-pharmacological treatment (e.g., cognitive behavioural therapy, exercise, light therapy, etc.) or switching to a
neurostimulation treatment (such as electroconvulsive therapy or transcranial magnetic stimulation) can be considered. 3) If there is no improvement (defined as
b20% reduction in symptom score), switch to another antidepressant with evidence for superior efficacy (Table 4). If tolerability is an issue, switch to an
antidepressant with a different side effect profile. 4) If there is no or limited improvement with the second monotherapy, an add-on treatment is recommended.
5) If there is some improvement but remission has not been achieved with the first-line antidepressant, and depending on tolerability, use an add-on treatment
(adding another agent to the index antidepressant, Table 11). The selection of medication for add-on treatment should be individualized depending on efficacy,
side effect burden, and residual symptoms. 6) If there is limited response to add-on treatment, consider strategies for treatment-resistant depression (TRD). The
pharmacotherapy options include using another add-on agent, or switching to another first-line antidepressant with some evidence for superiority, or to second
and third-line antidepressants including TCAs (especially clomipramine), quetiapine, or MAO inhibitors. 7) After achieving full symptom remission, patients
should be maintained on antidepressants for at least 6–9 months before stopping. Patients with risk factors for recurrence (Table 12) should have a personalized
assessment for maintenance treatment. Most should be maintained on their antidepressant for at least 2 years and some may require lifetime maintenance. The
dose of antidepressant for maintenance treatment should be the same as that required for acute treatment.
3.13. How effective is the strategy of adding an augmentation of antidepressants, including TCAs and SSRIs
“augmentation” agent? (Crossley and Bauer, 2007). Two RCTs found superiority of
lithium over placebo in augmentation of SSRIs and in an RCT
Augmentation add-on strategies are among the best of relapse prevention following open-label augmentation of
validated pharmacological treatments for TRD. However, various antidepressants (including SSRIs) (Bauer et al., 2000),
conclusions are still limited by small sample sizes and lack although another placebo-controlled RCT involving lithium
of placebo controls. There are also few direct comparisons of augmentation of nortriptyline showed negative results
different augmentation strategies and little information about (Nierenberg et al., 2003). Lithium is recommended at dosages
the optimal duration of add-on strategies. of greater than 750 mg daily, or at a dose that achieves serum
There is Level 1 evidence to support lithium augmenta- levels in the therapeutic range (0.5–1.0 meq/L). A suggested
tion. The most recent meta-analysis (10 RCTs, N = 269 dosage schedule is 600 mg daily for 1 week, increasing to
participants) found it significantly superior to placebo in 900 mg daily for 1 week, and then titrating to adequate serum
S36 R.W. Lam et al. / Journal of Affective Disorders 117 (2009) S26–S43
RCTs did not find any superiority of the combination compared 3.17. How long do you keep patients on an antidepressant once
to either higher dose fluoxetine alone or to fluoxetine they are better?
augmented with low-dose lithium (Fava et al., 2002).
In summary, there is only Level 2 evidence to support Many RCTs and meta-analyses have shown that main-
efficacy of antidepressant combinations in non-responders to tenance medication effectively prevents recurrence of symp-
monotherapy (Table 11). The best available evidence is for toms with effects lasting from 6 months through 5 years. Two
add-on treatment with mirtazapine/mianserin or bupropion. meta-analyses have examined predictors of the maintenance
effect, and both had similar results: the effect size was not
3.15. What are the relative benefits of switching versus dependent on the risk factors for relapse (as well as could be
add-on treatment? determined), the duration of antidepressant treatment prior
to randomization, nor the time of the randomized follow up
Given the lack of trials comparing these strategies, most of period (Geddes et al., 2003; Hansen et al., 2008). One meta-
these factors are speculative. Switching to another monotherapy analysis confirmed that maintenance doses should be the
offers simplicity, in that there is no concern about drug same as the dose that got people better, as those randomized
interactions or additive side effects. With add-on medications, to dose reduction had higher relapse/recurrence rates than
especially another antidepressant, one can never be sure that those continuing on the same dose (Papakostas et al., 2007b).
the combination is necessary because any benefit may be due Only 1 RCT involving newer agents has prospectively
solely to the second agent. However, advantages of an add-on examined the length of time for maintenance. The PREVENT
strategy include faster onset of response (for some augmenta- trial entered patients with recurrent depression (defined as 3
tions) and the potential of a second agent to address specific or more episodes, two of which were in the past 5 years) who
residual symptoms and/or side effects. In addition, for some were treated to remission with venlafaxine for 6 months.
patients there may be a psychological advantage to adding a They were then randomized to maintenance venlafaxine or
second agent to “boost” the effect of the first, rather than placebo for 12 months, after which sustained remitters in the
switching and “giving up” on the first agent. Finally, it is well venlafaxine arm were re-randomized for another 12 months
recognized that a small percentage of patients are late (Keller et al., 2007). The recurrence rate was significantly
responders, requiring 8 weeks or longer for initial response. It lower in the venlafaxine-treated patients compared to
is very difficult for patients to continue taking a single agent for placebo after both follow up periods, indicating that main-
such a long time without any response, but adding a second tenance treatment for at least 2 years is beneficial for recurrent
agent allows a patient to continue longer on the first. depression [Level 2].
Since there are few comparative data available on the
merits of each of these strategies, it remains a clinical decision 3.18. Who should be maintained longer on an antidepressant?
weighing factors including the patient's past history and
degree of response, side effects to the index antidepressant, It is difficult to make specific recommendations for long
and the potential side effects of a new medication (Kennedy term antidepressant treatment. Personalized approaches with
et al., 2001). individualized application of available evidence, careful evalua-
tion of the benefits (prevention of recurrence) and the risks of
3.16. What is a rational, sequential approach for non-response continuing medication (e.g., side effects, cost) in each patient
or incomplete response to a first-line antidepressant? will be clinically more relevant than general recommendations.
Patients with risk factors (Table 12) require longer term
While there is considerable evidence to support the treatment for a minimum of 2 years and, for some, lifetime
efficacy of switch and add-on strategies, there is still little [Level 3] (Geddes et al., 2003; Hansen et al., 2008; Reynolds
information on how these strategies compare against each et al., 2006). Although empirical evidence is lacking, longer
other and how they should be sequenced. It should also be maintenance treatment should also be considered for patients
noted that most switch and add-on studies focus on TRD, with depression vulnerability factors including early onset
which is usually defined as treatment failure (b20% reduction depression, psychosocial adversity, and chronic medical ill-
in depression scores) after two or more adequate antide- nesses [Level 4]. MDD with other psychiatric comorbidities
pressant trials. There is very little information about effective including obsessive compulsive disorder or borderline person-
strategies for partial response (i.e., 20–49% reduction) or for ality disorder also may require long term treatment [Level 4].
residual symptoms (N50% reduction, but not in remission). In addition to clinical and demographic factors, certain
While the objective of the STAR*D effectiveness study was to biological (e.g., short allele of serotonin transporter gene
examine sequencing of treatments, the focus on non-remis- promoter region polymorphism) and psychological (e.g.,
sion did not allow differentiation between partial and non- neuroticism, cognitive vulnerability) markers have been
responders and, beyond the second treatment step, there was identified as possible risk factors for recurrence of MDD in
inadequate power to detect small but clinically meaningful the context of stress (Caspi et al., 2003). Longitudinal
differences between treatments. controlled studies are needed to establish the role of these
For these reasons, the recommended sequences are based markers in optimizing the length of antidepressant treatment.
primarily on expert opinion. Fig. 1 provides an algorithm for Besides antidepressants, cognitive behavioural therapy (CBT)
sequencing of treatments when there is inadequate response to has long-term effects in preventing relapses and recurrences
a first-line antidepressant. At each decision stage, it is useful to (Parikh et al., 2009). Hence, integrating CBT with antidepres-
evaluate the degree of improvement and side effect burden with sant treatment may shorten the term of antidepressant
validated rating scales in order to tailor subsequent treatments. maintenance.
S38 R.W. Lam et al. / Journal of Affective Disorders 117 (2009) S26–S43
If the decision is made to discontinue an antidepressant, it In two small RCTs designed to study prevention, non-
should be tapered off gradually to avoid discontinuation depressed women with a history of postpartum depression
symptoms [Level 3] (Schatzberg et al., 2006). The high risk were randomized to antidepressant or placebo immediately
patient should be monitored regularly for early signs of after childbirth; sertraline (Wisner et al., 2004) showed a
recurrence after discontinuation of antidepressants. preventative effect compared to placebo, but nortriptyline did
not (Wisner et al., 2001).
Special populations Data on antidepressant use during lactation are also
limited, especially on infant outcomes during long term
3.19. Which antidepressants can be used during pregnancy? follow up (Eberhard-Gran et al., 2006). Most studies of
mother–infant pairs show that antidepressants are excreted
Since the previous guidelines in 2001, there have been no into breast milk in varying and, usually, small amounts. In a
RCTs evaluating the safety and efficacy of antidepressants pooled analysis of 57 studies, infant serum levels of nortripty-
during pregnancy. The evidence remains limited to small line, sertraline and paroxetine were usually not detectable,
studies or case control/cohort designs, often with many while infants exposed to fluoxetine had higher risk of having
confounding variables and conflicting results. For example, elevated serum levels (Weissman et al., 2004). Although the
comparison groups usually include women who are not using pooled analysis also suggested that infants exposed to
antidepressants but who are not necessarily depressed, so citalopram may be at higher risk, especially if the mother's
potential adverse effects associated with depression itself are citalopram dose was high, subsequent prospective case series
not taken into account (Table 13). showed very low or undetectable infant serum levels (Berle
At least 7 meta-analyses examining safety of antidepres- et al., 2004; Heikkinen et al., 2002). One study followed
sants during pregnancy have been published since 2000. Some infants who had been exposed to antidepressant medication
concluded that SSRIs and newer antidepressants had no during lactation and reported no effects on infant weight up
associated risks of major (Einarson and Einarson, 2005; to 18 months postpartum (Hendrick et al., 2003).
Rahimi et al., 2006) or minor (Rahimi et al., 2006) malforma-
tions, but one found evidence that SSRI use late in pregnancy 3.21. Which antidepressants can be used for children
was associated with subtle adverse effects (serotonergic and/or adolescents?
overstimulation, withdrawal syndromes, long term neurobe-
havioural effects) in newborns (Lattimore et al., 2005). The Pharmacotherapy in youth (children and adolescents under
newer antidepressants are associated with an increased risk of age 18) with MDD has been a controversial topic because the
spontaneous abortions, although an effect of depression could benefits of antidepressants are less evident and the risks
not be ruled out (Hemels et al., 2005; Rahimi et al., 2006). The include increased suicidality (defined as worsening suicidal
use of SSRIs during late pregnancy also has been associated thoughts and self-harm behaviours) in this age group
with persistent pulmonary hypertension in newborns in some (Table 14). A previous meta-analysis of 12 RCTs assessing the
studies (Chambers et al., 2006) but not in others (Andrade et efficacy of TCAs in youth did not demonstrate efficacy and
al., 2009); meta-analyses are not currently available. therefore TCAs are not recommended in this age group (Hazell
For individual drugs, first trimester use of fluoxetine was not et al., 1995). Subsequent meta-analyses have shown favourable
associated with teratogenicity (Addis and Koren, 2000) while evidence of efficacy of SSRIs in youth with MDD (Tsapakis et al.,
first trimester use of paroxetine was associated with an 2008), especially with fluoxetine and citalopram (Usala et al.,
increased risk for cardiac malformation in one meta-analysis 2008; Wallace et al., 2006), but the effect sizes of antidepres-
(Bar-Oz et al., 2007) but not in another (O'Brien et al., 2008). sants are modest, with a number needed to treat (NNT) of 10 for
The authors of the first study acknowledged that detection bias clinical response (Bridge et al., 2007).
may have affected the results (Bar-Oz et al., 2007). In summary, In adolescents who did not respond to a first SSRI, there
antidepressants do not appear to be major teratogens but they were no differences in effectiveness or safety when switching to
may be associated with neonatal complications, usually another SSRI (citalopram, fluoxetine or paroxetine) compared
described as transient reactions. Further study is required of to venlafaxine, although the SSRI switch led to fewer adverse
longer term neurobehavioural effects in children exposed in events (Brent et al., 2008). However, the combination of
utero to these medications. medication and CBT resulted in the best outcomes.
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