Background
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No or insufficient levels of evidence addressing the question.
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Possibility to decline the topic in easily identifiable clinical situations.
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Need to identify and select the strategies deemed appropriate by an independent panel of experts from amongst several alternative therapeutic options.
Methods
Results
Expert panel: description
Reading rules
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Therapeutic strategies are organised around successive lines of treatment (from first to sixth) and, for each line, two levels of recommendations are provided, as first and second intentions, respectively
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Definitions of response, complete and partial remission, chronic depression, relapse and recurrence are provided in Additional file 3
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A classification of ADT is provided in Additional file 4
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Optimisation consists of increasing the dose of the treatment up to the maximally tolerated dose as recommended by the summary of the characteristics of the product.
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Potentiation consists of adding an originally non-ADT pharmacological agent in association with the ADT drug over a given period of time in order to obtain pharmacological synergy that may improve the therapeutic properties
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Association consists of combining two ADTs with distinct and complementary pharmacological profiles over a given period of time
Definition of resistant depression and at-risk situations
Based on clinical expert consensus, the definition of treatment-resistant depression adopted is the failure of two ADT of adequate duration and dose. The optimal duration is 4 to 6 weeks when the targeted dose is obtained
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Comorbid anxiety disorder
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Comorbid substance abuse
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Comorbid personality disorders
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Comorbid non-psychiatric chronic and organic disease
Assessments of treatment-resistant depression
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Clinician-rated and self-rated scales of depression severity
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Hypomania rating scale
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Suicide rating scale
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Complete blood count, blood electrolytes, liver and renal functions
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Lipid profile (cholesterol, triglyceride) and glucose levels
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Thyroid-Stimulating Hormone levels (TSHus)
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Plasma levels of ADT
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Electrocardiogram
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Brain MRI
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Pharmacogenetic testing for CYP enzymes
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Urinary and blood toxicological analysis
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Plasma cortisol determination
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Polysomnographic sleep assessment
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Electroencephalography
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Plasma levels of Vitamin D
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Sexual hormone levels
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Carbohydrate deficient transferrin determination
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C-reactive protein measurement
Principles of clinical and pharmacological management
Indications for hospitalisation
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High suicidal risk
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Presence of psychotic symptoms
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Severe forms of MDD
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Failure of three unsuccessful attempts of ADT
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Need for electroconvulsive therapy
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Risk of poor adherence to treatment
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Failure of two previous ADT
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Comorbidity with a severe medical condition
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Co-occurrence with other psychiatric disorders
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Lack of adequate familial support
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Intolerance to current medication
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Need for benzodiazepines withdrawal
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Need for monoamine oxidase inhibitors, transcranial magnetic stimulation or transcranial direct current stimulation
Adjuvant treatments
Treatments with an ADT action
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Selective serotonin reuptake inhibitors (SSRIs)
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Dual serotonin and norepinephrine reuptake inhibitors (SNRIs)
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Tricyclic ADT
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Irreversible, non-selective monoamine oxidase inhibitors (IMAOs)
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α2-antagonists
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Agomelatine
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Tianeptine
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In monotherapy: bupropion, selective and reversible IMAO-A, quetiapine
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In combination with an ADT: lithium, lamotrigine and second-generation antipsychotics
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For Major Depressive Disorder with a significant aboulia, anhedonia, psychomotor retardation or fatigue: SNRI
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For Major Depressive Disorder with a significant weight loss or significant sleep disturbances: α2-antagonist
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For Major Depressive Disorder with a marked depressed mood: tricyclic ADT
Minimal duration of ADT
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The presence of a comorbid psychiatric disorder.
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The presence of psychotic symptoms.
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The presence of high suicidal risk.
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Resistance to at least one ADT at adequate duration and dose.
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A history of early relapse after the treatment is discontinued.
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A long period before reaching remission.
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A history of at least 2 previous episodes of depression.
Pharmacological strategies in treatment-resistant depression
Switching strategies
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Concurrent switch: changes in the dose of both medications are implemented simultaneously. The new medication is gradually titrated upward while the current agent is gradually tapered downward.
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Overlapping switch: dose changes are only implemented for one medication at time, while holding the original medication constant at the original dose until the second medication has reached its optimal dose.
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Sequential switch: the dose of the current medication is titrated downward until the interruption. Then, the new medication is introduced.
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No response to the initial treatment
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Poor tolerance to the initial treatment
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Previous response to the newly introduced treatment
Combination strategies
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SSRI + α2 antagonist
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SNRI + α2 antagonist
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Tricyclic ADT + α2-antagonist
Add-on strategies
Potentiation Treatment | Target level: |
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1rst Intention | |
•Lithium | 0,5 à 0,8 mmol/La |
•Quetiapine | 50 à 150 mg/dayb |
2nd Intention | |
•Aripiprazole | 2,5 à 10 mg/dayc |
•Tri-iodothyronine | 25 à 50 μg/dayd |
•Lamotrigine | 200 à 400 mg/day |
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Physical examination
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Electrocardiogram
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Determination of Thyroid-Stimulating Hormone levels
Strategies to prevent relapse
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Regularly assessing treatment adherence
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Regularly assessing insertion and social functioning
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Regularly assessing the quality of life,
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Investigating possible illicit drug use.
Organisation of sequenced treatment
First-line strategy
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SSRIs and SNRIs are considered a first-line treatment, regardless of the clinical severity, without distinguishing between these types of ADT.
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For severe depression, psychotherapies are only recommended in combination with ADT, whereas they can be proposed in monotherapy in mild to moderate major depressive episodes.
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Tricyclic ADT, α2-antagonists or agomelatine can be proposed as a second-line treatment in severe depression.
Dimension | First Intention | Second Intention |
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With marked anhedonia | SSRI or SNRI | α2-antagonist or agomelatine |
With marked psychomotor retardation | SNRI. SSRI | Tricyclic or α2 antagonists |
With marked sleep disturbances | SSRI or SNRI or α2-antagonist or agomelatine | Tricyclic ADT |
With atypical features (hyperphagia, hypersomnia) | SSRI or SNRI | Tricyclic or agomelatine |
With psychotic features | SNRI in monotherapy or SSRI in combination with an atypical antipsychotic | SSRI, tricyclic ADT or α2-antagonist, in monotherapy or in combination with AAP |
With anxious features | SSRI or SNRI or α2 antagonist | Tricyclic ADT |
With high suicidal risk | SSRI or SNRI or α2 antagonist | Tricyclic ADT or potentiation strategies with lithium or AAP |
Second-, third-, fourth-, fifth- and sixth-line strategies
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If a patient has a partial response to the first-line ADT: association with an α2-antagonist is recommended irrespective of the class of the initial ADT (except for mianserine and mirtazapine)
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If a patient has non-response to the first-line ADT: switching strategies is recommended. Association of two ADT is not recommended in first intention.
Psychotherapy
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Provide psychological support
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Inform the patient about the disease and its overall characteristics and management
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Help the patient to gain a greater understanding of their own psychopathology
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Increase therapeutic alliance and adherence to pharmacotherapy
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Develop coping strategies for stressful situations
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Improve psychosocial functioning and quality of life
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Manage psychiatric comorbidities, in particular addiction and anxiety disorders
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Teach the patient to evaluate mood and recognise evidence for the occurrence of early symptoms or clinical worsening
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Cognitive behaviour therapy
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Supportive therapy
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Psychoeducational intervention
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Cognitive behaviour therapy
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Psychoeducational intervention
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Mindfulness therapy.