Treatment of depression

Article written and reviewed by Dr Luca Moretti

Treatment of depression requires an individualized approach that takes into account diagnosis, severity and duration of symptoms, functional impairment, suicide risk, psychiatric and medical comorbidities, previous treatments and patient preferences. The goal is not only to reduce symptoms, but, when possible, to achieve complete and sustained remission, promote recovery of personal, social and occupational functioning, and reduce the risk of relapse and new episodes.

Before starting treatment, it is essential to confirm the correct diagnostic framework. A depressive episode may occur in major depressive disorder, bipolar disorders, in relation to substance or medication use, or in the context of other medical conditions. In particular, current or previous manic or hypomanic episodes substantially alter the therapeutic strategy and require classification within the bipolar disorders.

Psychotherapy and pharmacotherapy are the main pillars of treatment and can be used alone or in combination. In less severe presentations, several psychological and behavioral strategies may be appropriate; antidepressants remain an option when consistent with the clinical characteristics and the patient's informed preference. In more severe presentations, psychotherapeutic, pharmacological or combined interventions are available from the outset, with intensity proportionate to severity and clinical urgency.

Treatment should be reassessed over time. A strategy that was initially appropriate may require modification in the event of an incomplete response, adverse effects, changes in clinical conditions or the emergence of new historical information. Modern management of depression is therefore a dynamic and shared process, not the automatic application of an identical treatment sequence to every patient.

Phases of treatment for depression

• The acute phase aims to reduce symptoms of the current episode and, ideally, achieve remission and functional recovery.
• The continuation phase consolidates the result obtained after response or remission and reduces the risk of relapse of the same episode.
• The maintenance phase is indicated when the risk of new episodes justifies long term continuation of a preventive strategy.

The duration of the different phases is not the same for everyone. The number of previous episodes, severity, duration, residual symptoms, previous suicidal behavior, comorbidities and functional consequences all contribute to determining how long treatment should continue after remission.

Pharmacotherapy

Antidepressants are one of the main therapeutic tools for major depressive disorder. Numerous agents from different pharmacological classes have demonstrated efficacy, but no single antidepressant is universally superior for all patients. Differences in average efficacy must be considered together with tolerability, safety, interactions, previous responses and individual characteristics.

The choice of pharmacological treatment should therefore take into account clinical history, treatments already used, comorbid conditions and other medications. The adverse effect profile, risk in overdose, age, reproductive considerations and patient preferences are also relevant. The presence of a single specific symptom generally does not allow prediction with certainty of which antidepressant will be most effective.

Second generation antidepressants, including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors and other agents with different mechanisms, are widely used because overall they provide a favorable balance of efficacy, tolerability and safety.

Tricyclic antidepressants are effective medications, but their greater anticholinergic, cardiovascular and sedative burden and greater toxicity in overdose generally limit their use as initial options compared with better tolerated agents.

Monoamine oxidase inhibitors retain a role in selected situations, including some depressive disorders that have not responded adequately to other treatments. Drug and food interactions and the need for specific precautions mean that their use is predominantly specialist based.

Medications from other classes may be added to an antidepressant when response is insufficient. lithium salts, which are fundamental in the treatment of bipolar disorders, can also be used as an augmentation strategy in some forms of treatment resistant unipolar depression, while some antipsychotics are used for augmentation in selected treatment resistant depressive disorders and, in combination with an antidepressant, in depression with psychotic features.

Antidepressant effects may begin to emerge progressively during the first weeks, but evaluating a treatment requires an adequate therapeutic trial in terms of dose, duration and adherence. Some adverse effects may appear earlier and should be discussed with the patient to prevent unplanned discontinuation.

When response is insufficient, the first step is to reassess diagnosis, possible bipolarity, adherence, dose, duration, substance use, drug interactions and medical or psychosocial conditions that may contribute to persistent symptoms. Apparent nonresponse does not necessarily represent true pharmacological resistance.

After this reassessment, several strategies may be considered: optimizing the current treatment, switching antidepressants, adding psychotherapy, or using a pharmacological combination or augmentation strategy. The choice also depends on the degree of benefit already obtained and the tolerability of the current treatment.

After remission, effective therapy is generally continued to reduce the risk of relapse. In patients with recurrent episodes, residual symptoms, particularly severe episodes or other unfavorable prognostic factors, a more prolonged maintenance treatment may be appropriate.

Antidepressant discontinuation should be planned individually and is generally carried out through gradual dose reduction. Discontinuation that is too rapid can cause discontinuation symptoms, which must be distinguished from recurrence of depressive symptoms.

Psychotherapy

Psychotherapy is a treatment with documented efficacy for depression and can be used alone or together with pharmacotherapy. Its position in the treatment pathway varies according to severity, clinical features, patient preferences, previous responses and accessibility of interventions.

In less severe presentations, psychological interventions are often a particularly appropriate initial option, while in more severe presentations they can be used alone or as part of combined treatment. On average, the combination of structured psychotherapy and an antidepressant is associated with a greater likelihood of response than either modality alone in several populations with depression, without implying that they must be combined in every patient.

Psychotherapy is not equivalent to generic emotional support. Validated techniques are structured interventions based on theoretical models and specific procedures, with defined goals and methods of application.

Cognitive behavioral therapy acts on cognitive and behavioral processes that may contribute to maintaining depression, while behavior therapy and behavioral activation approaches place particular emphasis on reducing avoidance and progressively restoring meaningful and rewarding activities.

Interpersonal therapy focuses treatment on relationships, role transitions, interpersonal conflicts and losses relevant to the depressive presentation, while brief psychodynamic therapy addresses recurring emotional and relational patterns through a structured, time limited psychodynamic intervention.

There is no single duration applicable to all psychotherapies. The number and frequency of sessions depend on the therapeutic model, severity, goals and clinical response. Patients with complex needs, comorbidities or residual symptoms may require a longer course than standard protocols.

Even after remission, some psychological interventions may contribute to relapse prevention. In particular, Mindfulness-Based Cognitive Therapy is a structured psychological intervention based on cognitive elements and mindfulness practices, studied primarily for prevention of recurrence in people with recurrent depression.

The efficacy of psychotherapy should not be reduced simply to the patient's “willpower” or motivation. Anhedonia, fatigue, pessimism, psychomotor slowing and cognitive deficits are part of depressive symptomatology and may make initial engagement more difficult, requiring a therapeutic approach adapted to the actual clinical condition.

Intensive biological treatments

More severe, treatment resistant forms or presentations characterized by particular clinical conditions may require somatic treatments capable of directly modulating the activity of brain circuits. The different techniques do not, however, have the same level of evidence or the same indications and are not interchangeable alternatives.

Electroconvulsive therapy, or ECT, remains one of the most effective treatments for severe depression. It is performed under general anesthesia using controlled electrical stimulation and may be considered when a rapid response is required, in presentations with psychotic or catatonic features, in the presence of severe clinical compromise, or when other treatments have not produced sufficient results.

ECT should therefore not be interpreted exclusively as a last line treatment. Its position in the treatment pathway depends mainly on severity, urgency, the benefit to risk profile, previous responses and patient preferences.

Repetitive transcranial magnetic stimulation uses magnetic fields to modulate activity in specific cortical areas and is a noninvasive form of neuromodulation with an established role, especially in patients who have not responded adequately to previous antidepressant treatments.

Transcranial direct current stimulation uses low intensity electrical currents applied through electrodes on the scalp. Evidence for antidepressant efficacy has progressively increased, but protocols, clinical indications and regulatory status are not uniform and depend on the device and healthcare context.

Among invasive techniques, vagus nerve stimulation involves implantation of a device capable of chronically stimulating the vagus nerve and is used, in certain healthcare systems, for selected forms of treatment resistant depression.

Deep brain stimulation instead requires neurosurgical implantation of electrodes in specific brain structures. In major depressive disorder, it is not currently a routine treatment and remains predominantly a research intervention in highly selected refractory cases.

Neuromodulation therefore encompasses interventions that differ greatly in invasiveness, evidence, speed of effect and therapeutic positioning. Selection always requires specialist assessment and cannot be determined simply by the number of previous treatment failures.

Emerging approaches and treatment personalization

In recent years, strategies have been developed that extend traditional monoaminergic models of antidepressant pharmacotherapy. Particularly important among these are interventions that modulate glutamatergic transmission and tools intended to improve treatment personalization.

Ketamine and esketamine act mainly through the glutamatergic system and can produce a rapid antidepressant response in selected patients. Intranasal esketamine has approved indications in specific conditions, whereas racemic ketamine is used according to specialist protocols and different regulatory frameworks. Both require careful patient selection and clinical monitoring.

The rapidity of the effect does not eliminate the need for an overall treatment strategy. Even when a rapid response is achieved, continuation and maintenance of benefit must be defined and safety, tolerability and the risk of symptom recurrence must be considered.

Psychedelics, particularly psilocybin administered within protocols with psychological support, are being studied clinically for depression. Available findings have generated considerable interest, but issues involving blinding, expectations, patient selection, duration of benefit and safety require further clarification; their use does not represent a routine antidepressant therapy that can be generalized broadly.

Pharmacogenetics studies the influence of genetic variants on drug response and metabolism. Certain gene drug pairs can provide useful information, particularly regarding pharmacokinetics and tolerability, but available tests cannot reliably predict which antidepressant will be clinically most effective in an individual patient.

Treatment personalization therefore remains primarily clinical: previous response, episode characteristics, course, comorbidities, adverse effects and preferences carry greater weight than any single biomarker currently available.

Integrative therapies

Management of depression also includes lifestyle interventions and complementary strategies that can accompany the main treatments. It is important, however, to distinguish interventions supported by consistent clinical evidence from those whose role remains ancillary or poorly defined.

Physical activity has evidence of efficacy for depressive symptoms and can be integrated into the treatment program, selecting a type, intensity and frequency compatible with the patient's physical condition and abilities. In presentations characterized by severe fatigue or psychomotor slowing, activity should be introduced progressively and not presented as a simple motivational prescription.

Regularizing the sleep wake rhythm, reducing problematic alcohol and other substance use, treating concomitant physical illnesses and maintaining an adequate social network contribute to comprehensive care. These interventions do not automatically replace psychotherapy or pharmacotherapy when those treatments are clinically indicated.

Nutraceutical interventions include very different substances. Omega-3, folates, vitamin D, S-adenosylmethionine and other compounds have been studied mainly as complementary strategies, but efficacy, quality of evidence and indications vary considerably and do not support attributing uniform efficacy to the entire category.

Music therapy can be used as a complementary intervention within structured treatment programs, and some studies indicate possible benefits for depressive symptoms, although the evidence is more limited than for the main psychological and pharmacological treatments.

Animal assisted interventions, commonly referred to as pet therapy, have also been studied in specific contexts for possible effects on relationships, social engagement and emotional well being. Available evidence is heterogeneous, however, and does not support their use as a substitute treatment for major depression.

Mindfulness-Based Cognitive Therapy, although it includes mindfulness practices, should be distinguished from generic meditation techniques: it is a structured psychotherapy with evidence particularly relevant to prevention of depressive recurrence.

Relapse prevention is in fact a fundamental part of treatment. After remission, residual symptoms, the number and severity of previous episodes, comorbidities, previous relapses after discontinuation and the patient's ability to recognize early warning signs should be assessed.

Follow up should simultaneously monitor symptoms, functioning, adverse effects, adherence and physical and psychosocial conditions. In patients at high risk, prolonged maintenance treatment, pharmacological, psychotherapeutic or combined, may be indicated, with periodic reassessment of the balance between benefits and possible disadvantages.

Overall, treatment of depression should therefore integrate scientifically documented efficacy, safety, clinical characteristics and individual preferences. Medications, psychotherapies, somatic treatments and complementary interventions occupy different positions in the treatment pathway and should be selected according to the clinical presentation, avoiding both rigidly standardized sequences and combinations without a defined rationale.

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