Refractory depression is not yet standardized, but is generally considered to be a part of monophasic depression without psychotic symptoms that has been treated with at least two antidepressants of different mechanisms of action in adequate doses (upper limit of treatment) and for adequate courses (at least 6 weeks) with poor or no efficacy.
Although difficult to treat, it is not an incurable disease and there are ways to improve treatment outcomes. For depressed patients with poor treatment results, the first thing to do is to determine if the depression is refractory: see if the course of treatment is sufficient, if it has reached 6 to 8 weeks, if not, continue to observe and extend the treatment time first; then see if the dose of medication is sufficient, if not, increase the dose as appropriate, perhaps the effect will appear after the increase. If it is not effective even after sufficient dose and treatment, it is necessary to take a new history and psychiatric examination to determine whether it is depression, and if it is depression then switch to antidepressants with a different mechanism of action, such as TCAs for SSRIs, SSRIs for SNRIs, or NARIs (norepinephrine reuptake inhibitors), or NaSSAs, or NDRIs (selective DA/NE reuptake inhibitors). Gradually increase the dose to the full amount and maintain it for a sufficient duration, and if it is still ineffective or has poor efficacy, the depression may be designated as refractory.
Once refractory depression has been identified, the following regimens may be applied for treatment.
(I) booster program
1.Lithium booster
Lithium booster is a common booster regimen in the treatment of refractory depression. This regimen is based on the neurobiological hypothesis that the combination of tricyclic antidepressants with lithium can increase the efficacy, but there is a lack of evidence-based evidence on the benefit of adding lithium booster. It is generally accepted that the starting dose of lithium is set at 600 mg/d and observed for 4 to 6 weeks before efficacy is assessed. In addition, some studies have found that lithium treatment reduces the risk rate of suicide and reduces the excess mortality of affective disorders (monophasic, bipolar, schizoaffective) to the normal range.
2.Thyroxine potentiator
Depression is closely related to abnormal thyroid function, and many patients have hypothyroidism or subclinical hypothyroidism. Since the 1960s there have been many reports on the use of thyroxine to increase the efficacy of antidepressants to treat depressed people who have not been treated with antidepressants alone. It has been reported that the highest efficacy with the addition of thyroxine booster was up to 53%, while the highest efficacy with the addition of placebo was only 19%. With the addition of thyroxine booster, a small number of patients may have increased anxiety and may experience hypersensitivity, tachycardia, insomnia, and sweating. For those with cardiac insufficiency or elderly patients, thyroxine should be used with caution.
3. Dopaminergic potentiators
Evidence from both preclinical and clinical studies suggests that dopamine may play a role in the pathogenesis of depression; therefore, dopaminergic agonists such as bromocriptine, amantadine and pramipexole for the treatment of Parkinson’s disease may have antidepressant effects whether used as monotherapy or adjunctive therapeutic agents.
4.Butrocyclone potentiator
Studies have shown that the anxiolytic drug buspirone can enhance 5-HTergic nervous system activity through presynaptic membrane 5-HT1A self-receptor desensitization and postsynaptic 5-HT1A or 5-HT2 downregulation, thus producing antidepressant effects. Some authors believe that buspirone combined with citalopram is a safe and effective method for the treatment of refractory depression.
5. Mirtazapine booster
An open study of the efficacy of mirtazapine booster SSRIs reported that 15 to 30 mg of mirtazapine taken at bedtime was effective. This result was confirmed by a later placebo-controlled study. In addition, mirtazapine booster may also deal with sexual dysfunction due to SSRIs.
6. Atypical antipsychotic potentiators
Although many authors recommend risperidone, olanzapine, quetiapine and other atypical antipsychotics as potentiators for depressed patients who have failed SSRIS treatment, evidence-based evidence is still lacking.
7. Other drugs that can be used as potentiators
The antiepileptic drugs lamotrigine, sodium valproate, carbamazepine, and sex hormones such as estrogen and testosterone have been used as antidepressant potentiators, but their effectiveness needs to be further evaluated.
(ii) Combination treatment options
In the case of refractory depression, the term combination regimen refers to the combination of two antidepressants. There is much evidence for the combination of MAOIs and TCAs or SSRIs and TCAs in the treatment of refractory depression. It is important to note that neither SSRIs, venlafaxine, duloxetine, nor clomipramine should be used in combination with MAOIs.
(iii) Other options
Other treatments such as the application of electroconvulsive therapy followed by antidepressant consolidation therapy; antidepressants combined with psychotherapy. In addition, the combination of Chinese and Western medicine is a promising treatment option.