In 2009, the Canadian Network for Mood and Anxiety Treatments (CANMAT), a non-profit scientific and educational organization, published a review of evidence-based clinical guidelines for the treatment of depressive disorders. CANMAT updated these guidelines in 2016 so that new evidence is reflected in practice.
The target of these guidelines continues to be the adult population with unipolar major depressive disorder (MDD) , aimed at psychiatrists and other mental health professionals. CANMAT, in collaboration with the International Society for Bipolar Disorders , has published separate guidelines for bipolar disorder. This section on "Drug Treatments" is one of the 6 sections of the 2016 CANMAT guideline.
These recommendations are presented as a guide for physicians, who should consider them in the context of each patient and not as standards of care. Some medications discussed may not be available in Canada or other countries.
| Methods |
The question-answer format was used. A systematic literature search was conducted focusing on systematic reviews and meta-analyses. The evidence was graded using the CANMAT-defined criteria for level of evidence. Recommendations for treatment lines were based on the quality of the evidence and the consensus of expert clinicians.
> Who should receive pharmacological treatment?
The effectiveness of antidepressants for MDD has been confirmed. In 2009, it was established that second-generation antidepressants are first-line treatments for moderate or severe major depressive episode (MDE).
For mild depression, psychoeducation, self-management and psychological treatments are recommended. Pharmacological treatment may be considered for mild depression, in certain situations such as patient preference; a previous response to antidepressants or lack of response to non-pharmacological interventions.
> What antidepressants have recently been approved?
Since 2009, several medications have been approved: Levomilnacipran , a derivative of milnacipran, a serotonin and norepinephrine reuptake inhibitor (SNRI), more selective in inhibiting norepinephrine than serotonin, compared to other IRSs. One study showed that it does not prevent relapses. Vilazodone is a multimodal antidepressant that acts as an IRS. In a study against placebo it showed greater efficacy, using doses of 20 mg and 40 mg. It has not been compared with other antidepressants.
It is recommended to stagger doses to avoid gastrointestinal adverse effects. Vortioxetine , another multimodal antidepressant, acts in several ways : as an IRS, a 5-HT1A receptor agonist, a partial 5-HT1B receptor agonist, and an antagonist of 5-HT1D, 5-HT3A, and 5-HT1B receptors. HT7. Vortioxetine also has positive effects on neuropsychological performance in multiple cognitive domain processes in patients with MDD1. Vortioxetine has been proven to be superior to placebo.
> How is an antidepressant selected?
The process of selecting an antidepressant should involve both the physician’s experience and the patient’s perceptions and preferences. The selective serotonin reuptake inhibitors (SSRIs) agomelatine, bupropion and mirtazapine, as well as vortioxetine are the recommended first-line agents for the pharmacotherapy of MDD. Second-line agents, due to their adverse effects, are tricyclic antidepressants (TCA), quetiapine and trazodone.
Moclobemide and selegiline are also second choices due to their possible serious interactions, while levomilnacipran is second choice due to the lack of comparative prevention and data on relapses); Vilazodone is also included due to the lack of comparative and relapse prevention and the need to titrate and take with food.
Third-line medications include monoamine oxide inhibitors (MAOIs) (due to a higher burden of adverse effects and potential severity of drug and dietary interactions) and reboxetine (lower efficacy).
Many clinical and medicinal characteristics influence the choice of a first-line antidepressant. If there are absolute or relative differences between the drugs, they are small. Therefore, selection involves evaluating the individual needs of each patient.
> What clinical factors influence the selection of antidepressants?
The influencing factors are: older age, presence of anxiety and long duration of the episode. These factors are associated with worse response to medications. However, the evidence on clinical characteristics is of low quality and there is no evidence to support specific antidepressant recommendations. There is no consistent evidence regarding age, sex, race, or ethnicity to predict the outcomes of use of specific antidepressants. Other proposed parameters are: episode and course that allow specifying the subtypes of clinical presentations of MDD.
Other proposed clinical dimensions are cognitive dysfunction, sleep disturbance and somatic symptoms. Large trials examining response with specifiers (melancholic, atypical, anxious) found no differences in efficacy between escitalopram, sertraline and venlafaxine XR, or between escitalopram and nortriptyline. No difference was found in remission rates with citalopram in the atypical and melancholic subtypes: Antipsychotic antidepressants showed greater efficacy than placebo for psychotic depression.
Mixed functions are a new DSM-5 specifier for major depression, and no trials have used these DSM-5 criteria. For MDEs with mixed DSM-5-like symptoms, monotherapy with lurasidone and ziprasidone was found to be more effective than placebo.
Bupropion, duloxetine, moclobemide, and tianeptine improve domains of learning, memory, and executive function. Some antidepressants, (agomelatine, mirtazapine, trazodone) and quetiapine have shown superior effects on subjective or objective measures of sleep. However, mirtazapine, quetiapine, and trazodone also have the highest rates of daytime sedation and drowsiness adverse events.
> How do psychiatric and medical comorbidities act? Do they influence the selection of antidepressants?
There is little evidence to guide the choice of antidepressants in the management of MDD with comorbid conditions. The new recommendations are similar to those for the treatment of comorbid mood and anxiety disorders, attention-deficit/hyperactivity disorder, substance use disorders, personality disorders, metabolic disorders, and common medical conditions.
> How do second generation antidepressants work? Comparison of effectiveness
The 2009 CANMAT guideline established that some antidepressants have superior efficacy, although the differences were small. Meta-analyses continue to show that some antidepressants have modest superiority in treatment response, particularly escitalopram, mirtazapine, sertraline, and venlafaxine.
> How do antidepressants compare on functional outcome measures?
CANMAT recommendations for assessing functional outcomes highlight the critical impact of depressive symptoms on social, occupational, and physical functioning, and that recovery from depression involves both relief of symptoms and improvement in functioning. Functional outcomes correlate only modestly with symptom outcome, and functional improvement may fall short of symptom improvement.
80% of antidepressant treatment studies reported symptom outcomes only. There is no conclusive evidence regarding the association of antidepressants with cognitive improvement and general functioning. There is no evidence of superiority of one antidepressant over another, regarding these domains.
> What is the comparative tolerability of second generation antidepressants?
It is very difficult to compare the tolerability of antidepressants, as well as their adverse effects on sexual function. Some comparisons of low-quality studies are shown in the original.
> Are antidepressants associated with suicide?
Suicidal ideation and acts are important risks associated with MDD and require diligent evaluation, monitoring, and management during psychiatric treatment. The studies carried out in this regard have given discordant results, although those predominating speak of a reduction in the risk of suicidal ideas, behavior and acts (the latter in those >65 years of age.
> What are the rare but serious side effects of antidepressants?
Prolongation of the corrected QT interval (QTc) is a surrogate marker of Torsade de Pointes (TdP) arrhythmia. It has been proven with citalopram, escitalopram and quetiapine. However, TdP is often an idiosyncratic event, and its associations with antidepressants, medication dosage, and QTc prolongation remain unclear. Most TdP cases occurred with therapeutic doses.
In the long term, SSRIs have been associated with an increased risk of falls and fractures unrelated to postural hypotension. Hyponatremia is also associated with SSRI use, primarily in the elderly with other risk factors for hyponatremia. SSRIs can inhibit platelet aggregation by altering serotonin receptors and moderately increasing the risk of gastrointestinal bleeding. Elevation of liver enzymes is rare with most antidepressants.
> Are there differences in the formulations of antidepressants?
No differences have been found in the efficacy or tolerability of extended-release antidepressants compared to immediate-release formulations, although with the latter there was some evidence of low adherence. Extended-release antidepressants are indicated when medication adherence or compliance is problematic. Substituting a brand-name drug for a generic drug is common practice in some countries and may involve alternative formulations.
Lack of bioequivalence can lead to loss of efficacy or increased side effects and, in some cases, has led to the discontinuation of an approved generic agent. Although generic medications are safe and reliable for most patients, a careful risk-benefit assessment (taking into account the potential loss of effectiveness) should be made before switching to a brand-name, proven reliable medication.
> What is a clinically relevant drug-drug interaction
Many patients with MDD take other medications for psychiatric and medical comorbidities. Drug-drug interactions can potentially reduce the effectiveness of an antidepressant or other medications and increase adverse effects.
Most antidepressants bind to several CYP enzymes, but agomelatine and duloxetine are primarily metabolized through the CYP1A2 pathway and should not be coadministered with medications that inhibit CYP1A2, such as cimetidine, ticlopidine, and ciprofloxacin. The same happens with vilazodone, which, when metabolized through CYP3A4, can be altered by the prescription of CYP3A4 inhibitors such as ketoconazole.
Several antidepressants and atypical antipsychotics act as inhibitors of specific CYP isoenzymes. Clinically, relevant drug interactions are usually caused by agents that are potent CYP inhibitors, such as fluoxetine, paroxetine, and fluvoxamine. Drug-drug interactions with moderate CYP inhibitors, including bupropion, duloxetine, and sertraline, are rarely clinically relevant except at the highest doses.
There is no consistent evidence of clinically relevant interactions of P-glycoprotein (an important component of the blood-brain and gut barriers and affects the passage of drugs) with antidepressants or antipsychotics. However, when serotonergic or sympathomimetic drugs are combined with MAOIs they can lead to serotonin syndrome and/or hypertensive crisis.
Serotonin syndrome is rare except in cases of overdose, but can also occur with combined use of multiple serotonergic medications.
> Can pharmacogenetic or therapeutic tests help monitor drug level and thus select or optimize the antidepressant?
Although pharmacogenetic tests for CYP enzymes already exist, their availability is limited and CANMAT does not recommend their use. Nor does it recommend routine titration of the level of second-generation antidepressants due to the poor correlation between blood levels and clinical response. It would only be useful in certain cases (intolerance of minimum doses, repeated failure in response to high doses and detection of non-adherence.
> How long is the response to an antidepressant expected?
Early improvement (>20%-30% reduction from baseline) on a depression rating scale after 2-4 weeks correlates with response and remission at 6-12 weeks. Lack of early improvement at 2 to 4 weeks is also a predictor of non-response to antidepressant/non-remission. However, the evidence supporting early switching (2-4 weeks) in non-responders is low. In these cases, CANMAT recommends increasing the dose. If the patient does not tolerate it, change to another antidepressant.
> How long do you continue taking an antidepressant?
The CANMAT guidelines identify 2 phases for the treatment of depression: an acute phase (symptomatic remission) and a maintenance phase (prevention of relapses and recurrences). The 2009 recommendations are that antidepressants should be continued for 6-9 months after symptomatic remission, while, in those with risk factors for recurrence, antidepressant treatment should be extended to ≥2 years. New evidence supports this recommendation. There are studies that found benefits with maintaining treatment for up to 12 and 24 months, especially if there are clinical risk factors.
Up to 40% of patients who abruptly discontinue antidepressant medications may experience discontinuation symptoms, described by the FINISH mnemonic ( flu-like symptoms , insomnia, nausea, imbalance, sensory disturbances, hyperarousal) . nausea, imbalance, sensory disturbances, hyperarousal).
These symptoms are generally mild and transient, but more severe symptoms have been described. Immediate-release formulations of paroxetine and venlafaxine are the most likely to be associated with the effects of discontinuation, while medium-long-acting agents such as fluoxetine and vortioxetine are the least likely. Unless there are clinical reasons to the contrary, slowly reducing the dose is recommended when discontinuing antidepressants.
> How is an inadequate response to an antidepressant managed?
There is substantial evidence that many patients receive subtherapeutic doses and/or inadequate duration of treatment, and up to 20% may have poor adherence. Therefore, the diagnosis should be reevaluated and issues that may be affecting the therapeutic response considered. Psychotherapy and neurostimulation should also be considered for patients with an inadequate response.
There is a great lack of consensus on the concept and definition of treatment-resistant depression (TRD). There are few studies that address residual symptoms. There are also no conclusions about changes from SSRI treatments to other antidepressants of a different class. The value of switching to another class of medication or to another medication within the same class remains controversial. The following questions summarize the subsequent evidence for these strategies.
> How effective are the change strategies?
Evidence up to 2009 shows that switching from one antidepressant to another in the face of lack of response results in good response and remission rates, supported by studies with newer antidepressants. Only 3 randomized controlled trials compared the strategy of making the switch while continuing with the same antidepressant.
These studies did not find differences in response or remission rates nor were there definitive conclusions regarding the strategy of adding an antidepressant of the same class, without discontinuing the original. It was also not conclusive whether there was a difference when switching from one SSRI to another or a non-SSRI antidepressant. The value of switching between classes or within the same class of antidepressants remains controversial. Consequently, CANMAT continues to recommend switching to an antidepressant with evidence of greater effectiveness.
> How effective are complementary strategies?
A complementary (adjunctive or adjuvant) strategy refers to the addition of a second drug to the initial medication. Recommendations for adjuvant agents are based on efficacy and tolerability. Many medications were compared with placebo, but only aripiprazole, lithium, quetiapine, and triiodothyronine were more effective than placebo. The strongest efficacies were for aripiprazole and quetiapine. There were no differences between the active treatments, but the design of the studies reduces the power of indirect comparisons and the reliability of the results.
• Atypical antipsychotics. Adjuvant treatment with atypical antipsychotics has the most consistent evidence of efficacy in DRT. In the studies carried out, the most effective adjuvant medications, compared to placebo, were aripiprazole, olanzapine, quetiapine and risperidone. Other studies found no differences in efficacy between atypical antipsychotics. Randomized controlled trials tested the efficacy of the adjuvant brexpiprazole and ziprasidone.
• Antidepressants . The complementary strategy was examined by adding another antidepressant to an existing one for the treatment of DRT. The studies carried out are too heterogeneous but there was a signal of efficacy of the adjuvants mirtazapine/mianserin. It has been proven that the addition of an adjuvant antidepressant increases adverse effects, especially mirtazapine/mianserin or TCAs added to SSRIs. Little is known about the interactions between antidepressants and other medications that patients use due to their comorbidities. It is not recommended to use combinations of antidepressants when starting DRT treatment.
• Other medications . So far, there is not enough evidence of the effectiveness of adding lithium to antidepressant treatment. No augmentation (adjuvant added) studies have been performed with triiodothyronine. In the STAR.-D trial. Triiodothyronine was better tolerated than lithium and had lower dropout rates.
Modafanil, an atypical stimulant (studied in only 4 trials) used in MDD, showed marginal evidence of efficacy compared to placebo. Adverse effects do not appear to differ from placebo. Lisdexamfetamine, a very little-studied stimulant, is effective as an adjuvant agent for partial responders to SSRIs. However, in 2 other trials, the results were negative.
On the other hand, other stimulants only have negative studies. Single intravenous doses of ketamine have a rapid antidepressant effect in MDD. However, ketamine is associated with psychotic mimetic adverse effects and has potential for abuse.
There is still very little data on safety and effectiveness with long-term use. CANMAT considers ketamine an experimental treatment and recommends limiting its use to academic treatment in specialized centers. A meta-analysis found no benefit of pindolol vs. placebo in combination with SSRI therapy, and without differences in tolerability or safety. Pindolol is not recommended as adjunctive treatment.
> How to choose between switching to another antidepressant and adding an adjuvant agent?
One study found that, in terms of effectiveness, adjuvant aripiprazole was superior to switching from the antidepressant. In a retrospective comparison of STAR-D and adjunctive studies, patients who tolerated citalopram and responded were more likely to benefit from adjunctive strategies compared with switching. Some studies have addressed residual symptoms, such as fatigue or sexual dysfunction. However, there is no consistent evidence supporting specific adjuvant agents to target specific residual symptoms or side effects.
In summary, given the limited evidence, a pharmacological approach to DRT requires diagnostic reassessment, consideration of previous medication trials (including degree of response and tolerability), rational use of complementary medications, discontinuation of medications that have not been proven. had beneficial and careful monitoring of symptoms, side effects and functioning, to evaluate the results. The decision between the change and adjuvants must be focused individually.
> How is persistent depression and chronic depression managed?
The DSM-5 has added a new diagnosis, persistent depressive disorder (PDD), which includes the DSM-IV diagnoses dysthymic disorder and chronic MDD. A systematic review and network meta-analysis examined the efficacy (response) and acceptability (all-cause discontinuation) of treatments for PDD > 2 years in duration.
Most of the drugs studied were more effective than placebo, including fluoxetine, paroxetine, sertraline, moclobemide and imipramine, with no differences in acceptability. The only differences between treatments were greater efficacy of sertraline over imipramine and greater acceptability of moclobemide over fluoxetine. Uh meta-analysis showed that SSRIs had similar efficacy but greater tolerance than TCAs.
Network meta-analysis also identified differences in effects between combined psychotherapy plus medication and medication alone studies, in studies of dysthymia compared to studies of chronic MDD, suggesting that new diagnosis of PDD may not have a response to treatment. homogeneous. Although there are positive results from treating chronic depression and PDD with antidepressants, some experts have argued that patients with repeated treatment failures and a chronic course of depression require chronic disease management (i.e., with less emphasis on remission of symptoms and healing and greater emphasis on improving functioning and quality of life, and greater use of non-drug psychotherapeutic treatments.
> What novel treatments are being investigated?
The link between the rapid antidepressant effect of ketamine and the glutamate system has stimulated the development of related compound drugs, including esketamine (the senantiomer of ketamine, administered intranasally), lanicemine, and memantine. Other promising compounds are GluN2B antagonists. Others are directed at glutamate receptors. Drugs targeting the endocannabinoid system and drugs with neuroplasticity mechanisms are being studied, which are believed to play a role in sustained antidepressant effects.
Preliminary studies have shown several promising medications available. Adjuvant celecoxib provides higher response and remission rates, and lower dropout rates, compared with placebo.
In contrast, a subsequent small trial of female patients with first-episode MDD demonstrated no efficacy of adjuvant celecoxib added to sertraline. Preliminary studies of pramipexole, an agonist of dopamine D2, D3, and D4 receptors, have shown efficacy in bipolar depression and also some benefit for TRD. Other drugs investigated for MDD include newer atypical antipsychotics, such as cariprazine.
Conclusions Evidence-based pharmacological treatments are available for the first-line treatment of major depressive disorder and for the management of inadequate response. However, given the limitations of the evidence base, pharmacological treatment of major depressive disorder still depends on the patient’s adaptation to treatments. |
