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Treatment Guidelines for Treatment-Refractory Depression

These are currently being revised (November 2014). Please revisit this page for the latest version.

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Physical treatment methods

As a guiding principle, all of the physical treatments that have been shown to be effective in ‘treatment-resistant-depression’ (preferably in randomised, controlled trials) must have been tried in adequate dosage for an adequate period. In general terms, this will reflect the prescription of antidepressant drugs within, or above, the dose range recommended by the British National Formulary (BNF) for a period of at least six weeks.

It is important to note that a proportion of individuals with chronic, refractory depression will have unrecognised or ‘undeclared’ Bipolar Disorder. Therefore, the following also considers the application of “bipolar depression” treatment strategies as part of the framework for treatment ‘adequacy’ prior to ablative NMD.

At present, the use of plasma drug concentration monitoring (where possible) is not included as a mandatory requirement, but is sometimes desirable. Most patients referred for assessment will have been exposed to many different treatment trials. The following represent those deemed ‘essential’ before proceeding to ablative surgery.

The minimum inclusion criteria for neurosurgery are:

  1. At least two ‘adequate’ courses of treatment with a tricyclic antidepressant drug. One of these trials should ideally be with either clomipramine, imipramine or amitriptyline.
  2. At least two ‘adequate’ courses of treatment with a selective serotonin re-uptake inhibitor (SSRI).
  3. At least one ‘adequate’ course of treatment with a ‘classical’ monoamine oxidase inhibitor (i.e. not Moclobemide).
  4. At least one of the above (TCA, SSRI or MAOI) plus lithium carbonate augmentation for a period of 4-6 weeks with a 12-hour post-medication plasma lithium level of 0.5-0.8 mmol/L.
  5. At least one ‘adequate’ course of treatment with a tricyclic antidepressant drug as defined above plus thyroid hormone augmentation for a period of 6 weeks. This involves the administration of liothyronine sodium/ T3 hormone (not T4) [at a dose up to 20 micrograms three-times-a-day.]. Failure to respond within 6 weeks ought to lead to termination of T3 administration. Where the patient is known to suffer from hypothyroidism and is taking replacement T4 (biochemically euthyroid), this strategy of T3 augmentation is still advised.
  6. At least two ‘adequate’ courses of treatment with an antidepressant drug as defined above, plus the prescription of two atypical antipsychotic drugs for a period of six weeks at a dose within the BNF recommended range. There is probably greatest evidence to support the selection of olanzapine and risperidone, although others (quetiapine, amisulpride, aripiprazole) may be worth considering. Where psychotic symptoms are prominent in the clinical presentation, trials of both typical (e.g. Flupentixol) and atypical antipsychotic drugs should be considered.
  7. At least two ‘adequate’ trials of electroconvulsive therapy (ECT), spaced 6 months apart. Adequacy in this context is defined as a minimum of 12 bilateral applications of ECT with recorded evidence of seizure duration exceeding 15 s per treatment. Failure to respond is defined as either no clinical response, minimal clinical response or a brief response with relapse within a period of four weeks, despite adequate antidepressant maintenance treatment. Where available, and considered more acceptable/appropriate for the patient, a trial of high dose unilateral ECT (5 times seizure threshold) can substitute for bilateral ECT.
  8. At least one ‘adequate’ course of treatment with an SSRI as defined above plus the addition of bupropion (Sustained Release) at a dose of 150-300mg/day.
  9. At least one trial of an anticonvulsant drug shown to have efficacy in bipolar depression. This includes Lamotrigine at a dose of <400mg day, Divalproex sodium (Depakote®) at a dose of up to 2.5g per day and Carbamazepine at a dose of 800-1200mg per day.
  10. At least one trial of an antipsychotic drug shown to have efficacy in bipolar depression. This includes olanzapine (5-20mg/day) and quetiapine (300-600mg /day). NB there is also some preliminary evidence for increased response rates in the treatment of Bipolar I depression where olanzapine (6-12mg/day) is combined with fluoxetine (25-50mg/day).

Alternative Recommended Pharmacological Treatment Strategies 

Desirable but not essential prior to ablative NMD. Either: an absence of unequivocal evidence of efficacy in TRD, or, only suitable for selected patients on the basis of increased risk to physical health:

Prescription of an antidepressant drug beyond BNF recommended maximum daily dose.

  1. For example, gradual escalation to highest tolerated dose of venlafaxine (>500 mg / day). Beyond 375 mg / day, weekly ECG recordings are advisable, with regular BP monitoring required beyond 200 mg / day.
  2. Alternatively, gradual escalation to highest tolerated dose of imipramine (>300 mg / day). Similar close physiological monitoring is required. Measurement of plasma levels may be indicated, with a target concentration of 200-250 ng/ml. This ought to be continued for 6 weeks.
  3. Combination of venlafaxine (375mg/day or maximally tolerated dose) with mirtazapine (30-45mg/day) with appropriate physiological monitoring (BP measurements and ECG recordings)

Psychostimulant Drug Treatment

  1. Prescription of a maximally tolerated dose of a tricyclic drug (preferably imipramine), to which methylphenidate (Ritalin®) is added, initially as a single 10 mg test dose, gradually increasing to 30 mg t.d.s. This ought to be continued for 6 weeks.

Psychological Treatment Methods

  1. A range of therapies have an evidence base for the treatment of depression. These include:
    1. Behavioural Activation (BA);
    2. Interpersonal Therapy (IPT);
    3. Cognitive-Behavioural Therapy (CBT);
    4. Cognitive-Behavioural Analysis System of Psychotherapy (CBASP);
  2. For an individual to be considered refractory to a robust trial of psychological/behavioural therapy, they should have had an extended trial (typically in excess of 20 hours of therapy) delivered by someone either accredited by the BABCP, or with demonstrable experience and expertise in the treatment modality being delivered. At this point in time it is not possible to specify that treatment should have been given with one modality over another, but a good relationship with the therapist and high fidelity to the treatment model are important factors in assessing the robustness of the course of treatment.
  3. If there is any doubt over the adequacy of psychological therapy, referrers are advised to contact us to discuss the treatment in more detail.

Last Updated on Saturday, 15 November 2014 17:46

National Services Scotland

Advanced Interventions Service
Area 7, Level 6
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Ninewells Hospital and Medical School
Dundee, DD1 9SY. UK.
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