Treating Depression When First and Second Line Treatments Don't Work

Treatment Resistant Depression

Treatment resistant depression, also known as treatment-resistant major depressive disorder or TRD, refers to a condition in which a person's depression fails to respond adequately to conventional antidepressant medications or psychotherapeutic treatments despite adequate dosage and duration. When a person does not experience significant improvement or complete remission of depressive symptoms after two or more antidepressant treatment attempts, they are considered to have treatment-resistant depression.

Causes and Risk Factors for Treatment Resistance

The exact causes of treatment resistance in depression are still not fully understood. However, several factors are believed to increase the risk of a person developing treatment resistant depression:

- Genetics: Family history of Treatment Resistant Depression or a history of poor response to antidepressants increases the risk. Specific gene variations may play a role.

- Brain changes: Structural or functional abnormalities in areas of the brain like the prefrontal cortex and hippocampus that are linked to mood regulation may underlie treatment resistance.

- Chronicity of depression: People who have suffered from recurrent or chronic depression for many years are more likely to have treatment resistant symptoms.

- Medical conditions: Certain illnesses like thyroid disorders, autoimmune diseases, and cancer are linked with poorer antidepressant responses.

- Substance abuse: Concurrent alcohol or drug abuse can interfere with antidepressant effectiveness and increase treatment resistance.

Evaluating Treatment Resistance

When a person does not experience an adequate response after two antidepressant treatment attempts, a thorough evaluation is needed to best understand the cause of treatment resistance. The evaluation involves:

- Checking for diagnosis changes: Evaluating if the diagnosis should be changed to another mood disorder like bipolar disorder which requires different treatment.

- Assessing adherence: Ensuring the person is following treatment as prescribed in terms of dosage, duration and compliance with psychotherapy if prescribed. Non-adherence can result in resistance.

- Identifying medical illnesses: Ruling out medical conditions that can either directly cause or exacerbate depression.

- Reviewing treatment history: Considering how well past treatments worked and ensuring the current treatment is adequate in terms of drug selection, dosage and duration.

- Conducting lab tests: Checking tests like thyroid function to rule out influencing medical issues. Genetic testing may someday help identify treatment strategies.

- Gathering additional information: Collateral information from family and a comprehensive psychosocial history to identify risk factors or potential triggers for poor response.

- Screening for substance abuse: Assessing use of alcohol, drugs and other addictive substances which can reduce treatment effectiveness.

Once a thorough evaluation is completed, treatment resistance severity is determined to help guide next-step management decisions.

Augmenting Antidepressant Treatment

For people who have not had an adequate response to two or more antidepressants, the next line of treatment involves augmenting the ongoing antidepressant with a secondary agent to enhance the antidepressant effect. Some common augmentation strategies include:

- Adding atypical antipsychotics: Second generation antipsychotic drugs like aripiprazole, quetiapine, risperidone and olanzapine are frequently used as they have shown to improve response rates when paired with antidepressants in TRD.

- Using lithium or lithium augmentation: Lithium remains one of the most effective and studied augmentation agents. It can increase response rates substantially when added to ongoing antidepressant therapy in TRD.

- Adjunctive thyroid hormone: Use of thyroid supplements like triiodothyronine or thyroxine may enhance antidepressant effects in certain people with TRD, especially those with underlying thyroid abnormalities.

- Adding non-tranquilizing anti-convulsants: Drugs like valproate, carbamazepine and lamotrigine may augment antidepressants in TRD. Their mechanisms of action target neurotransmitter and neuronal pathways implicated in depression.

- Utilizing pramipexole or buspirone: These atypical agents show promise as augmenting options based on pilot studies and case reports, though large trials are still needed. They have unique mechanisms of action.

Choosing an augmenting agent depends on factors like past antidepressant response pattern, risk of side effects, practical issues like cost and a person's overall clinical profile and preferences. Regular monitoring is required to assess response. Most people need at least 4-8 weeks of augmentation to fully experience benefits. Switching the augmenting drug or combining two augmenting agents ('augmentation of augmentation') are subsequent steps if single augmentation fails to provide a satisfactory response.

Other Treatment Options for Treatment Resistant Depression

For individuals who remain significantly depressed despite multiple medication and psychotherapy augmentation attempts, alternative strategies that warrant consideration include:

- Repetitive transcranial magnetic stimulation (rTMS): A noninvasive procedure that uses magnetic fields to stimulate nerve cells in the brain to improve depression symptoms. Multiple clinical trials support its effectiveness when medications fail for TRD.

- Electroconvulsive Therapy (ECT): Delivering controlled electric currents through the brain to trigger brief seizures and induce neuroplastic changes. ECT remains one of the most effective therapies available for severe treatment resistant depression with high remission rates.

- Vagus Nerve Stimulation (VNS): Involves surgically placing a device similar to a pacemaker under the skin in the chest area to electrically stimulate the vagus nerve in the neck, aiming to induce antidepressant effects. Studies show moderate effectiveness in TRD.

- Deep Brain Stimulation (DBS): A highly experimental procedure involving surgical implantation of electrode stimulating devices in specific deep brain regions to relieve TRD. Ongoing research investigates safety and efficacy.

- Ketamine infusions: Subanesthetic doses of ketamine administered by intravenous infusion over 40 minutes often provide rapid antidepressant effects within hours to a few days in TRD patients. However, effects are mostly transient requiring repeated infusions for maintenance.

The choice of next step depends on a person's prior treatments, clinician's expertise, support system availability, risks versus benefits, and individual preference. Combination therapy involving two or more modalities together may also maximize outcomes. Ongoing case management also supports ongoing wellness and quality

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