Depression Management

Principles of therapy 

The goals of treatment include the following:

• Remission of all signs and symptoms of depression and restoration of functioning (acute phase of treatment)
• Reduction of likelihood of relapse and recurrence (continuation phase of treatment)
• Prevention of occurrence of new episode of depression and suicide (maintenance or stabilization phase of treatment)
• Resolving residual symptoms (eg fatigue, cognitive impairment, anhedonia, anxiety)
• Restoration of occupational, psychosocial and interpersonal function

The choice of treatment modality is based on the following factors:

• Symptom severity, either mild, moderate or severe
• Presence of comorbidities or psychosocial stressors
• Preference of the patient
• History of prior treatment

In treating depression, it must be remembered that psychiatric management should be provided if available. Different treatment modalities may be used to treat the acute phase of depression, including psychotherapy, pharmacologic therapy, pharmacologic therapy combined with psychotherapy, neurostimulation therapy, and psychoeducation of both the patient and the patient’s family.

Psychotherapy or Pharmacologic Therapy Alone

Either psychotherapy or pharmacologic therapy may be used alone if a patient has mild to moderate depression. Psychotherapeutic interventions may benefit the patient who presents with significant psychosocial stressors, interpersonal difficulties, etc.  

Psychotherapy Combined with Pharmacologic Therapy

This combination of treatment modalities may be useful for patients with moderate to severe depression, and/or those suffering from psychosocial issues, interpersonal problems or a personality disorder. This may also benefit patients who have failed single-treatment and those who may have compliance issues.  

Neurostimulation Therapy

Neurostimulation therapy may be considered in patients with high degree of functional impairment and severe symptoms. It may be useful in patients with psychotic symptoms or catatonia. This modality may be considered if there is an urgent need for response (eg patient refusing food and nutritionally-compromised, suicidal patient). 

Pharmacological therapy 

It must be noted that use of antidepressants may induce worsening of depression and may increase the risk of suicidal ideation and behavior in children.  

Principles of Therapy

In starting pharmacologic therapy, it must be remembered that there is no single medication that has been proven to be more effective than others. The choice of agent will be based on side effect profile, prior response history of patient or family member, patient preference, cost, presence of comorbidities, concurrent medications, and risk of death from overdose. Start with a low dose of the drug, then titrate to full therapeutic dose gradually. If side effects occur, the initial approach is to either decrease the dose of the drug or to shift to another antidepressant not known to cause the same adverse effect. It is recommended that antidepressant (eg selective serotonin reuptake inhibitors [SSRIs], serotonin and norepinephrine reuptake inhibitors [SNRIs], serotonin modulators, tetracyclic and tricyclic antidepressants) dose be increased in patients who do not improve after 2-4 weeks of treatment. Withdrawal symptoms (eg vertigo, dizziness, altered sensations, altered feelings, restlessness, agitation, insomnia, sweating, palpitations, headaches, tiredness) may occur in patients who abruptly stopped, missed doses or did not take a full dose of antidepressants. 

First-line Agents

Selective Serotonin Reuptake Inhibitors (SSRIs)

Example drugs: Citalopram, Escitalopram, Fluoxetine, Fluvoxamine (also a sigma 1 receptor agonist), Paroxetine, Sertraline  

SSRIs are the preferred choice for major depression due to fewer side effects compared to the older antidepressants (eg tricyclic antidepressants [TCAs] and monoamine oxidase inhibitors [MAOIs]). These drugs inhibit the reuptake of serotonin and normalize serotonergic imbalances. Different selective reuptake inhibitors inhibit serotonin reuptake to different extents. The onset of action of these drugs is usually around 2-4 weeks. However, for Escitalopram, onset of action is 1 week.  

Dopamine Norepinephrine Reuptake Inhibitor (DNRI)

Example drug: Bupropion  

DNRI is an alternative for patients who develop sexual dysfunction with other antidepressants. It inhibits the reuptake of dopamine and is a weak blocker of norepinephrine and dopamine reuptake. The onset of action of the drug is 1-4 weeks. 

Melatonergic Agonist

Example drug: Agomelatine  

Agomelatine acts as an agonist at melatonin receptors that are thought to provide beneficial effects upon sleep disturbances by helping to restore normal circadian rhythms. A study has shown that it has a better tolerability over SSRIs or Venlafaxine.  

Multimodal Serotonin Modulator

Example drug: Vortioxetine  

Vortioxetine inhibits reuptake of serotonin (5-HTO), and also has agonist activity at the 5-HT_1A receptor and antagonist activity at the 5-HT₃ receptor. A study with older adult patients showed that Vortioxetine had significant effects on verbal learning, memory, thought processing speed, and executive function compared to placebo, while studies for younger adults showed beneficial effects of Vortioxetine on objective and subjective measures of cognitive function.  

Noradrenergic and Specific Serotonergic Antidepressant (NaSSA)

Example drug: Mirtazapine  

Mirtazapine is an alternative for patients who do not respond to TCAs or SSRIs. It is useful in patients who are suffering from anxiety or insomnia. Mirtazapine blocks presynaptic adrenergic α₂ receptors resulting in an enhanced release of noradrenaline and serotonin. The enhanced serotonergic transmission is mainly via 5-HT₁ receptors as Mirtazapine blocks 5-HT₂ and 5-HT₃ receptors. The onset of action is 1-4 weeks.  

Noradrenaline Reuptake Inhibitor (NRI)

Example drug: Reboxetine  

Reboxetine has inhibitory effect on the reuptake of norepinephrine, weak effect on serotonin reuptake, but no significant effect muscarinic receptors. The onset of action is 1-4 weeks.  

Reversible Inhibitors of Monoamine Oxidase Type A (RIMAs)

Example drug: Moclobemide  

Moclobemide is less likely to cause hypertensive reactions to foods because of the selective, reversible type of inhibition. It has been studied in patients with seasonal pattern and cognitive dysfunction but needs more evidence.  

Selective Serotonin Reuptake Enhancer (SRE)

Example drug: Tianeptine  

Tianeptine is an option for patients who suffer from depression with anxiety. It increases the presynaptic reuptake of serotonin and may reverse the impairment of brain structural plasticity induced by depression. A meta-analysis showed that Tianeptine is at least as effective as SSRIs but with better acceptability profile.  

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

Example drugs: Desvenlafaxine, Duloxetine, Levomilnacipran, Milnacipran, Venlafaxine  

SNRIs inhibit the reuptake of norepinephrine and serotonin, while also weakly inhibiting dopamine reuptake. Clinical studies have shown that an 8-week duration of treatment established efficacy of Desvenlafaxine over placebo in adult patients diagnosed with major depressive disorder. Studies involving Duloxetine have shown the drug to be more effective than placebo for the treatment of depression. A meta-analysis showed that Venlafaxine extended-release may produce higher remission rates than SSRIs after 8 weeks of treatment. Venlafaxine is also an option for patients who suffer from depression and anxiety. Pooled analysis on Levomilnacipran showed efficacy for response and remission. The onset of action of these drugs can be as short as 1 week.  

Serotonin Modulators

Example drugs: Nefazodone, Trazodone, Vilazodone  

These drugs are alternatives for patients who experience sexual dysfunction with other antidepressants. They are also useful in patients who suffer from anxiety or insomnia. Serotonin modulators inhibit reuptake of serotonin at presynaptic neurons and antagonize post-synaptic 5-HT₂ receptors. Nefazodone additionally inhibits the reuptake of norepinephrine and blocks α₁-receptors. The onset of action is 2-4 weeks.

Second-line Agents

Irreversible, Nonselective Monoamine Oxidase Inhibitors (MAOIs)

Example drug: Selegiline  

MAOIs are considered as second-line agents because of their side effect profile, and their drug-food interactions limit their use. However, they may be particularly effective in patients who present with atypical features (eg reactive moods, reversed neurovegetative symptoms, sensitivity rejection) or in patients who have failed response to other antidepressants. The onset of action is 2-4 weeks.  

Second-generation (Atypical) Antipsychotics

Example drugs: Aripiprazole, Brexpiprazole, Olanzapine, Quetiapine, Risperidone  

Several studies have been published supporting their use as augmentation agents with antidepressants for treatment-resistant depression. Atypical antipsychotics may increase the rates of remission of depressive symptoms in patients who have not responded to >2 medication trials, including those without psychotic symptoms. The atypical antipsychotics that have been reviewed for this use include Aripiprazole, Brexpiprazole, Olanzapine, Quetiapine, and Resperidone.  

Tetracyclic Antidepressants

Example drugs: Maprotiline, Mianserin  

Maprotiline inhibits the reuptake of norepinephrine and has a weak affinity for central adrenergic receptors. Mianserin blocks presynaptic α₂ receptors, increases turnover of brain norepinephrine, and antagonizes serotonin receptors in the brain. Tetracyclic antidepressants have similar effects to TCAs except with fewer muscarinic side effects (and fewer cardiac side effects with Mianserin) but there is a marked sedative effect.  

Tricyclic Antidepressants (TCAs)

Example drugs: Amitriptyline, Amoxapine, Clomipramine, Desipramine, Dothiepine, Doxepin, Imirpamine, Nortriptyline, Protriptyline  

TCAs inhibit the reuptake of norepinephrine in the central nervous system (CNS), some in addition, inhibit the reuptake of serotonin. TCAs also act on histaminic and muscarinic receptors resulting in unwanted side effects. These side effects and their potential for fatal overdose limit their use. The onset of action is 2-4 weeks.  

Other Agent

Example drug: Gepirone  

The mechanism of Gepirone is not yet fully understood but is thought to have selective 5-HT_1A receptor agonist activity resulting in serotonin modulation in the CNS. This drug has just been recently approved by the United States Food and Drug Administration (US FDA) for the treatment of major depressive disorder.  

Augmentation Therapy

Augmentation therapy may be considered for partial responders and for those who are treatment resistant. Antidepressant medications can be combined with a depression-focused psychotherapy, either as an initial treatment plan or as a method to address nonresponse to one treatment modality. Antidepressant therapy can also be augmented by other non-MAOI antidepressants or with other non-antidepressant agents. One option is the addition of a second non-MAOI antidepressant from a different pharmacological class. Another option is the addition of an adjunctive non-antidepressant agent (eg Lithium, second-generation [atypical] antipsychotic).  

Benzodiazepine  

Benzodiazepines may be considered as an adjunct in patients with anxiety, depression or insomnia. It is advised that they not be used for longer than 2-4 weeks to avoid dependency.  

Lithium  

Lithium is a mood stabilizer used to augment antidepressant therapy. It is the most extensively studied among adjunct therapeutic agents. Several placebo-controlled studies have demonstrated positive evidence of efficacy of lithium, while clinical studies showed that mood stabilizers boost the effect of other antidepressants. It may be initiated when depression had not been alleviated by several antidepressants.  

Thyroid hormones  

Thyroid hormones may increase the effectiveness of antidepressant medication treatments, even in euthyroid patients. The typical dose used is 25 mcg/day of Triiodothyronine. Dose may be increased to 50 mcg/day after a week if response is inadequate.  

Treatment-Resistant Therapy

Example drugs: Esketamine, Ketamine  

Esketamine is an S-enantiomer of racemic Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist. These drugs are given in patients who have failed ≥2 of standard antidepressants or may improve partially but symptomatically do not remit or that full functional status has not been regained. Nasal spray can be used as an adjunct to oral antidepressants in patients with treatment-resistant depression.  

Alternative Therapy

St John Wort  

St John wort is an alternative option for patients in whom pharmacotherapy or psychotherapy are ineffective.

Nonpharmacological

Supportive Care

Patient Education  

In managing patients with depression, it is important to educate both the patient and the family members on the disorder to prevent stigmatization and underestimation of the severity of major depression. Counsel both on the treatment goals, treatment options, psychotherapy, choice of drug, side effects, and the time to see effect.  

Exercise  

It must be noted that regular exercise, resistance or aerobic, may be effective in relieving symptoms, particularly among older adults and those with comorbidities, provided there is no medical contraindication, with yoga being a recommended form of exercise. Around 3-5 sessions per week of 45-60 minutes of moderate intensity exercises for 10-12 weeks duration is recommended for children and young adults.  

Acupuncture  

This may be considered as an add-on to antidepressant medications in the treatment of mild to moderate depression.  

Psychotherapy

This is the initial choice of treatment for mild to moderate major depressive disorder. It is also the treatment of choice for pregnant patients or those who desire pregnancy. The type and optimal frequency of therapy should be individualized based on factors such as treatment goals, symptom severity, comorbidities, patient preference, and availability. Psychotherapy is also indicated for patients with partial response or who have compliance problems with antidepressant therapy. This is done in combination with antidepressants in patients with moderate to severe depression.  

Cognitive Behavioral Therapy (CBT)  

The goal in CBT is to reduce depressive symptoms by challenging irrational beliefs and distorted images of the self and to reverse these beliefs and attitudes. CBT is recommended for patients with residual symptoms or for those who have relapsed despite treatment with antidepressants. It is effective in the treatment of both major and minor depression.  

Interpersonal Therapy (IPT)  

The therapy is geared towards identifying the present triggering factor for the episode with the goal of resolving interpersonal problems (eg role disputes, social isolation, prolonged grief, role transition). The efficacy of IPT has been shown among pregnant, postpartum women, adolescents, elderly, and the prevention of relapse.  

Psychodynamic Psychotherapy  

Psychodynamic psychotherapy focuses on the therapist-client relationship as a vehicle for revealing and resolving interpersonal difficulties. The goal is to determine underlying conflicts in both past and present interpersonal relationships.  

Problem-Solving Therapy  

The goal in problem-solving therapy is to develop appropriate coping behaviors for problems. This modality is appropriate for patients with mild depression.  

Dialectical Behavioral Therapy (DBT)  

DBT consists of individual therapy sessions and DBT skills group that aim to find ways to hold opposite perspectives at once by promoting balance and avoiding the all-or-nothing styles of thinking. It was initially developed for the treatment of borderline personality disorder, but research shows effectivity in depressed elderly patients. DBT is a comprehensive, evidence-based, cognitive-behavioral intervention.  

Couple or Marital and Family Therapy  

This is considered for patients with significant marital or family distress.  

Group Therapy  

Data supporting group therapy in major depressive disorder is presently lacking.  

Neurostimulation Therapy

Electroconvulsive Therapy (ECT)  

ECT has the highest success rate among antidepressant treatments. It is the treatment of choice for severe major depressive disorder unresponsive to pharmacological treatment and/or psychotherapy. It is also recommended that for geriatric depression, patients with high degree of functional impairment, life-threatening symptoms (eg suicidal patients) or with psychotic symptoms, and for those who desire ECT or have had positively responded to ECT. It should only be administered by an experienced specialist; it is usually given 2-3 times per week. During the acute phase, there would be 6-12 rounds of treatments, usually <20. The total course should maximize symptom remission.  

Repetitive Transcranial Magnetic Stimulation (rTMS)  

rTMS makes use of pulsed magnetic fields to produce electrical stimulation of superficial cortical neurons. This is approved for patients with major depressive disorder unresponsive to at least one antidepressant treatment.  

Deep Brain Stimulation (DBS)  

DBS involves implanting electrodes under MRI guidance into discrete brain targets. It is currently being investigated as a treatment option for treatment-resistant major depressive disorder.  

Vagus Nerve Stimulation  

Vagus nerve stimulation is an option for patients with depression unresponsive to medications and/or electroconvulsive therapy. However, it is not indicated during the acute phase of treatment. It has a potential in long-term treatment of depression, but its role remains a subject for debate.  

Chronotherapy

Light Therapy  

Light treatment is a well-established treatment for major depression with a seasonal specifier that uses bright light. It is also used as augmentation therapy for antidepressant treatment of nonseasonal depression. A study has shown that 5 weeks of adjunctive bright light therapy with gradual advance timing protocol resulted in a more rapid remission and higher cumulative rate of remission of depression, especially in chronotyped depressed patients. Light therapy has the effect of accelerating the effect of antidepressants.  

Wake Therapy (Sleep Deprivation)  

Wake therapy is used for the treatment of depressed patients who do not take antidepressants. It helps potentiate the effects of antidepressant therapy. Wake therapy is used as an adjunctive treatment for more severe and refractory forms of depression in combination with other chronotherapeutic modalities.