Depression Treatment

Goals of Treatment

• 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

Choice of treatment modality is based on the following factors: 

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

Treatment modalities that may be used to treat the acute phase of depression:

Psychiatric management should be provided if available

• Psychotherapy
• Pharmacological therapy
• Pharmacological therapy combined with psychotherapy
• Neurostimulation therapy
• Psychoeducate the patient and family

Psychotherapy or Pharmacological Therapy Alone

• Either modality may be used alone if patient has mild to moderate depression
• Patient preference for psychotherapy or pharmacological therapy
• Psychotherapeutic interventions may benefit the patient who presents with significant psychosocial stressors, interpersonal difficulties, etc

Psychotherapy Combined with Pharmacological Therapy

• May be useful for patients with moderate to severe depression
• Patient suffers from psychosocial issues, interpersonal problems or a personality disorder
• May benefit patients who have failed single-treatment modalities
• Patient preference
• Patients who may have compliance issues

Neurostimulation Therapy

• May be considered in patients with high degree of functional impairment and severe symptoms
• May be useful in patients with psychotic symptoms or catatonia
• May be considered if there is urgent need for response (eg patient refusing food and nutritionally-compromised, suicidal patient)
• Take into account patient preference

Principles of Pharmacological Therapy

• No single medication has been proven to be more effective than others
• 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, risk of death from overdose
• Start with a low dose of drug and titrate to full therapeutic dose gradually
• If side effects occur, initial approach is to either decrease the dose of the drug or shift to another antidepressant not known to cause the same adverse effect
• It is recommended that antidepressant (eg SSRIs, SNRIs, serotonin modulators, tetracyclic and tricyclic) dose be increased in patients who are nonimprovers 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 the antidepressants

Use of antidepressants may induce worsening of depression and may increase the risk of suicidal ideation and behavior in children

First-line Agents

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Eg Citalopram, Escitalopram, Fluoxetine, Fluvoxamine (also a sigma 1 receptor agonist), Paroxetine, Sertraline
• Preferred choice for major depression due to fewer side effects as compared to the older antidepressants [eg tricyclic antidepressant (TCA) and monoamine oxidase inhibitor (MAOI)]
• Inhibits the reuptake of serotonin and normalizes serotonergic imbalances
  • Different selective serotonin reuptake inhibitors inhibit serotonin reuptake to different extent
• Onset of action: 2-4 weeks; 1 week for Escitalopram

Dopamine Norepinephrine Reuptake Inhibitor

• Eg Bupropion
• An alternative for patients who develop sexual dysfunction with other antidepressants
• Inhibits the reuptake of dopamine and is a weak blocker of norepinephrine and dopamine reuptake
• Onset of action: 1-4 weeks

Melatonergic Agonist

• Eg 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 have shown it to have better tolerability over SSRIs or Venlafaxine

Multimodal Serotonin Modulator

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

Noradrenergic and Specific Serotonergic Antidepressant (NaSSA)

• Eg Mirtazapine
• An alternative for patients who do not respond to tricyclic antidepressants or selective serotonin reuptake inhibitors
• Useful in patients suffering anxiety or insomnia
• Blocks central presynaptic adrenergic α₂ receptors resulting in an enhanced release of noradrenaline and serotonin
  • The enhanced serotonergic neurotransmission is mainly via 5-HT₁ receptors as Mirtazapine blocks 5-HT₂ and  5-HT₃ receptors
• Onset of action: 1-4 weeks

Noradrenaline Reuptake Inhibitor

• Eg Reboxetine
• Inhibits the reuptake of norepinephrine, weak effect on serotonin reuptake and no significant effect on muscarinic receptors
• Onset of action: 1-4 weeks

Reversible Inhibitors of Monoamine Oxidase type A (RIMAs)

• Eg Moclobemide
• Less likely to cause hypertensive reactions to foods because of the selective, reversible type of inhibition
  • Has been studied in patients with seasonal pattern depression and cognitive dysfunction but needs more evidence

Selective Serotonin Reuptake Enhancer (SSRE)

• Eg Tianeptine
• Option for patients who suffer depression with anxiety
• Increases the presynaptic reuptake of serotonin
  • May reverse the impairment of brain structural plasticity induced by depression
• Meta-analysis showed that Tianeptine is at least as effective as selective serotonin reuptake inhibitors but with a better acceptability profile

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

• Eg Desvenlafaxine, Duloxetine, Levomilnacipran, Milnacipran and Venlafaxine
• Inhibits the reuptake of norepinephrine and serotonin; also weakly inhibits dopamine reuptake
  • Clinical studies of 8-week duration established efficacy of Desvenlafaxine over placebo in adult patients diagnosed with major depressive disorder
  • Clinical studies have shown Duloxetine to be more effective than placebo for treatment of depression
  • Meta-analysis showed that Venlafaxine extended-release may produce higher remission rate than selective serotonin reuptake inhibitor after 8 weeks of treatment
  • Venlafaxine is an option for patients who suffer depression with anxiety
  • A pooled analysis on Levomilnacipran showed efficacy for response and remission
• Onset of action: Can be as short as 1 week

Serotonin Modulators

• Eg Nefazodone, Trazodone, Vilazodone
• An alternative for patients who experience sexual dysfunction with other antidepressants
• Useful in patients who suffer anxiety or insomnia
• Inhibits reuptake of serotonin at presynaptic neurons and antagonizes post-synaptic 5HT₂ receptors
  • Nefazodone inhibits reuptake of norepinephrine and blocks α₁-receptors
• Onset of action: 2-4 weeks

Second-line Agents

Irreversible, Nonselective Monoamine Oxidase Inhibitors (MAOIs)

• Eg Selegiline
• Considered as 2nd-line agents because of side effect profile and drug and food interactions limit their use
  • Maybe particularly effective in patients who present with atypical features (eg reactive moods, reversed neurovegetative symptoms and sensitivity rejection) or in patients who have failed response to other antidepressants

• Onset of action: 2-4 weeks

Tetracyclic Antidepressant

• Eg Maprotiline, Mianserin
• Maprotiline inhibits the reuptake of norepinephrine and has weak affinity for central adrenergic receptors
• Mianserin blocks presynaptic α₂ , increases turnover of brain norephineprine and antagonizes serotonin receptors in the brain
• Similar effects to tricyclic antidepressant except fewer muscarinic side effects (and fewer cardiac effects with Mianserin) but there is a marked sedative effect

Tricyclic Antidepressants (TCAs)

• Eg Amitriptyline, Amoxapine, Clomipramine, Desipramine, Dothiepin, Doxepin, Imipramine, Nortriptyline, Protriptyline 
• Inhibit the reuptake of norepinephrine in the central nervous system, some in addition, inhibit the reuptake of serotonin
• Tricyclic antidepressant also acts on histaminic and muscarinic receptors resulting in unwanted side effects
• Side effects and potential for fatal overdose may limit use
• Onset of action: 2-4 weeks

Other Agent

• Eg Gepirone
• Mechanism is not yet fully understood but is thought to have selective 5HT1A receptor agonist activity resulting into serotonin modulation in the CNS
• Recently approved by the US FDA for the treatment of major depressive disorder

Augmentation Therapy

• May be considered for partial responders and 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-monoamine oxidase inhibitor antidepressants or with other non-antidepressant agents:
  • One option is addition of a second non-monoamine oxidase inhibitor antidepressant from a different pharmacological class
  • Another option is the addition of an adjunctive non-antidepressant agent [eg Lithium, second-generation (atypical) antipsychotic]

Benzodiazepine

• May be considered as an adjunct in patients with anxiety, depression, or insomnia
• Advise to use for not longer than 2-4 weeks to avoid dependency

Lithium

• Mood stabilizer used to augment antidepressant therapy
  • Most extensively studied among adjunct therapeutic agents
  • Several placebo controlled studies have demonstrated positive evidence of efficacy
  • Clinical studies show that mood stabilizers boost the effect of other antidepressants
  • May be initiated when depression has not been alleviated by several antidepressants

Second-generation (Atypical) Antipsychotics

• Several studies have been published supporting their use as augmentation agents with antidepressants for treatment-resistant depression
  • May increase the rates of remission of depressive symptoms in patients who have not responded to >2 medication trials, including those without psychotic symptoms

• Atypical antipsychotics reviewed for this use include Aripiprazole, Brexpiprazole, Olanzapine, Quetiapine and Risperidone

Thyroid Hormones

• May increase the effectiveness of antidepressant medication treatments, even in euthyroid patients
• Typical dose used is 25 mcg/day of Triiodothyronine; may be increased to 50 mcg/day after a week if response is inadequate

Treatment-Resistant Therapy

• Given in patients who have failed ≥2 of standard antidepressants or may improve partially but symptomatically do not remit or full functional status has not regained

Esketamine

• A S-enantiomer of racemic ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist
• Nasal spray used as an adjunct to oral antidepressants in patients with treatment-resistant depression 

Alternative Therapy

St. John Wort

•  An alternative option for patients in whom pharmacotherapy or psychotherapy are ineffective

Exercise

• 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
  • Yoga is a recommended form of exercise
• 3-5 sessions per week of 45-60 minutes moderate intensity exercises for 10-12 weeks duration in children and young adults

Acupuncture

• May be considered as an add-on to antidepressant medications in the treatment of mild to moderate depression

Psychotherapy

• Initial choice of treatment for mild to moderate major depressive disorder
• Treatment of choice for pregnant patients or those who desire pregnancy
• Type and optimal frequency of therapy should be individualized based on factors such as treatment goals, symptom severity, comorbidities, patient preference and availability
• Also indicated for patients with partial response or who have compliance problems with antidepressant therapy
• Given in combination with antidepressants in patients who have moderate to severe depression

Cognitive-Behavioral Therapy (CBT)

• Goal is to reduce depressive symptoms by challenging irrational beliefs and distorted images of the self and to reverse these beliefs and attitudes
• For patients with residual symptoms or those who have relapsed despite treatment with antidepressants
• Effective in the treatment of major and minor depression

Interpersonal Therapy (IPT)

• Resolution of interpersonal problems (eg role disputes, social isolation, prolonged grief and role transition)
• Therapy is geared towards identifying the present triggering factor for the episode
• Efficacy has been shown among pregnant, postpartum women, adolescents, elderly and prevention of relapse

Psychodynamic Psychotherapy

• Focuses on the therapist-client relationship as a vehicle for revealing and resolving interpersonal difficulties
• Goal is to determine underlying conflicts in both past and present interpersonal relationships

Problem-Solving Therapy

•  Goal is to develop appropriate coping behaviors for problems
• Appropriate for patients with mild depression

Dialectical Behavioral Therapy (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
• Initially developed for treatment of borderline personality disorder but research shows effectivity in depressed elderly patients
• It is a comprehensive, evidence-based, cognitive-behavioral intervention

Couple/Marital and Family Therapy

• Consider for patients with significant marital or family distress

Group Therapy

• Data supporting its efficacy in major depressive disorder is presently lacking

Neurostimulation Therapy

Electroconvulsive Therapy (ECT)

• Has the highest success rate among antidepressant treatments
• Treatment of choice for severe major depressive disorder unresponsive to pharmacological treatment and/or psychotherapy
• Also recommended for patients with high degree of functional impairment, life-threatening symptoms (eg suicidal patients) or with psychotic or catatonic symptoms and for those who desire electroconvulsive therapy or have had positively responded to electroconvulsive therapy
• Should only be administered by an experienced specialist, usually given 2-3 times per week
• Acute phase involves 6-12 treatments, usually up to <20 treatments; total course should maximize symptom remission

Repetitive Transcranial Magnetic Stimulation (rTMS)

• Makes use of pulsed magnetic fields to produce electrical stimulation of superficial cortical neurons
• Approved for patients with major depressive disorder unresponsive to at least 1 antidepressant trial treatment

Deep Brain Stimulation (DBS)

• Involves implanting electrodes under MRI guidance into discrete brain targets
• Currently being investigated or experimented as treatment option for treatment-resistant major depressive disorder

Vagus Nerve Stimulation

• Option for patients with depression unresponsive to medications and/or electroconvulsive therapy
• Is not indicated for acute phase of treatment but has a potential in long-term treatment of depression
• Its role in the treatment of depression remains a subject of debate

Chronotherapy
Light Therapy

• Well established treatment for major depression with a seasonal specifier that uses bright light
• Also used as augmentation therapy for antidepressant treatment of nonseasonal depression
  • 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
  • Accelerate the effect of antidepressants

• Used for the treatment of depressed patients who do not take antidepressants
• Helps potentiate the effects of antidepressant therapy
• Adjunctive treatment for more severe and refractory forms of depression in combination with other chronotherapeutic modalities