Concept

The concept of treatment-resistant depression (TRD) has traditionally been grounded on unipolar depression. In a study published in the 60s, investigated reserpine’s role in treating “imipramine-resistant” patients. The concept of treatment-resistance considered in this study was “endogenous depression” with no improvement after at least 3 weeks of administration of imipramine, with daily doses up to 300 mg. The diagnosis of endogenous depression included: “prolonged pathological depressive emotional disposition, loss of interest and energy, psychomotor inhibition, sleep disturbances, anorexia with loss of weight, feeling of hopelessness, self-reproach, morning depression and an indication of suicidal tendencies.” The outcome was defined according to a clinical scale that included seven symptoms of depression, taking into account how long the improvement was observed, and it was categorized as follows: “good and stable improvement”; “good improvement lasting several days”; “transient of no improvement” ( ). included patients with depression, according to the Feighner criteria, who “had failed to respond to conventional treatment” in a trial with a pharmacological combination compared with electroconvulsive therapy (ECT) ( ; ). Despite the mentioned remission and response and the evaluation through psychometric scales, there is no objective definition of how the outcome was measured ( ). More straightforward inclusion criteria can be found in the study of De Montigny in which lithium was used for patients with depression who did not respond to tricyclic antidepressants after 3 weeks of treatment, meaning a decreased total scored in the Hamilton Depression Rating Scale (HDRS) less than 40% ( ; ). reported patients treated and followed in a Mood Disorder Clinic. The concepts the authors used are more closely aligned with what current studies usually consider, although their remission criteria, if used today, would be classified instead as response (50% decrease in the depression scores from the previous evaluation) ( ) ( Table 26.1 ).

More recently, the concept of resistance as nonresponse to at least two trials of antidepressants has become more frequent, and also it has been almost the rule for TRBD trials ( Table 26.2 ).

Table 26.2 provides a summary of TRBD definition according to different randomized controlled trials. This definition was refined by a consensus of internationally recognized experts in the field, resulting in a proposal for a multitherapy-resistant bipolar depression (MTRBD) concept ( ). These authors pointed out that a clear definition of TRBD could help guide when clinicians could consider novel and nonstandard interventions to treat patients. In summary, TRBD was defined as nonremission for 8 consecutive weeks after two different adequate trials of “at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment” for a patient with a current moderate or severe (bipolar) major depressive episode. MTRBD also requires “the addition of failure of at least one trial with an antidepressant, a psychological treatment and a course of electroconvulsive therapy.” The authors further include a list of the required medications, their adequate therapeutic dose ranges, minimum lithium plasma levels, and the characteristics of therapeutic trials of cognitive-behavioral therapy and the ECT (at least 12 sessions, bilateral) needed to satisfy MTRBD criteria ( ).

Frequency, adherence and guidelines compliance

Mendlewicz et al., for the Group for the Study of Resistant Depression (GSRD), investigated clinical factors associated with TRBD. Of 375 patients with BD type I or II who had received at least 4 weeks of adequate treatment with mood stabilizers and an antidepressant, 99 (26.4%) were classified as treatment-resistant. The criteria for TRBD considered for this study was a failure to reach a score of less than 17 in the Hamilton Depression Rating Scale (HAM-D 17) after at least two adequate consecutive antidepressant trials during the current episode ( ). A similar frequency was found in the study of . The authors investigated clinical predictors of TRBD, defined as lack of response to at least two established treatments for bipolar depression, with an exploratory-hypothesis generating approach. Fifteen of the 53 participants with BD type I or II filled the criteria per TRBD (28.3%) ( ). compared three groups of patients categorized according to the number of medications received regarding several demographic and clinical characteristics. Of the 1034 participants (128 with BD type I and 906 with BD type II), close to one-third of them had received five or more medications, the authors’ criteria as TRBD ( ). Despite no studies have addressed the prevalence of patients with BD and treatment-resistant depression; these findings suggest that about one-quarter to one-third of the patients would lack response to two or more pharmacological treatments.

Socio-demographic and clinical variables

investigated predictors of treatment-resistant in patients with bipolar depression. From the 53 individuals with bipolar depression, 15 (28.3%) had a history of lack of response to at least two adequate treatments for depression. The presence of mixed features, including symptoms such as increased energy, psychomotor activity, and irritability, correctly classified more than 70% of patients with TRBD ( ). Parker et al. reported a higher frequency of females among patients with TRBD (64%), early age of depression onset (17.3 years), and a considerable number of medical conditions considering the mean age of the sample (about three medical conditions in a sample with 38.6 years old on average). Psychiatric comorbidity burden was also sizeable: almost half presented generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder: Patients with TRBD also reported a substantial family history of psychiatric disorder (83.1% of depression and more than half of alcohol problems). Functional impairment was also highly-evident, as only 23% of the sample reported being engaged in full-time work ( ). found that patients with TRBD presented an odds ratio around twofold for the severe intensity of the last depressive episode, melancholic features, social phobia, and suicide risk.

Cognitive impairment has been recognized as a hallmark of BD and seems to be present regardless of clinical mood states ( ). Bo et al. reviewed cognitive performance in patients with BD compared to healthy controls (HC) using The Measurement and Treatment Research to Improve Cognition Schizophrenia Consensus Cognitive Battery (MCCB) ( ). Seven studies, including 467 patients with BD and 570 HC, were included in their meta-analyses, with results showing overall lower performance in all seven domains evaluated for the former group. The larger effect size was for processing speed (> 0.8), followed by visual and verbal learning (0.5), and social cognition, reasoning, and problem-solving (0.2) ( ). Kessler et al. evaluated neurocognitive function in patients with TRBD and investigated whether patients with types I and II would present distinct cognitive profiles. The authors found that both groups presented global impairment of clinically significant severity, which was more evident for BD type I, especially processing speed ( ).

Neurobiological characteristics

The neurobiological characterization of BD could help identify novel targets for intervention, optimizing the efficacy, safety, and broadening the array of options for its treatment. Moreover, it would facilitate the characterization of illness biotypes contributing to precise and personalized therapeutic strategies ( ). However, its etiology and pathophysiology are complex, involving several biological mechanisms, including dysfunctions in serotoninergic, noradrenergic, and glutamatergic systems, neurotrophic factors, inflammation, and external stressors, which challenges identifying critical pathways for intervention. Scaini et al. reviewed biological findings associated with BD, including genetic, biochemical, and neuroimaging ( ). According to this study, BD is highly heritable (70%–80%), and patients exhibit DNA methylation, alterations in the levels of micro-RNAs, and long noncoding RNAs, all potentially contributing to the phenotypic clinical presentation of the disease. Some studies also showed changes in brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and NT-4, which are associated with synaptic formation, neuronal growth, and regulation of neuronal survival processes ( ). Dysfunctions in the immune system and alterations on the inflammatory marker are also extensively found among patients with BD. Fernandes et al. reported increased C-reactive protein levels (CPR) in individuals with BD during all mood states, which were not associated with symptoms severity ( ). Postmortem studies showed inflammation in several brain regions, like the dorsolateral prefrontal cortex, anterior cingulate cortex, amygdala, and hippocampus ( ). Among the alterations, the authors reported those related to glial density and cytoarchitecture, and inflammatory gene and protein expression ( ). Excessive oxidative stress and mitochondrial dysfunction have also been found in patients with BD, as changes in mitochondrial morphology, high-energy phosphates and pH, and downregulation of proteins related to mitochondrial respiration ( ). Finally, neuroimaging studies have shown several structural and connectivity alterations in patients with BD compared with HC, as increased putamen volume, decreased volume of the amygdala, gray matter reductions in the insula, dorsolateral and orbitofrontal regions, and decreased connectivity in fronto-limbic tracts, cingulum, corpus callosum, and uncinate fasciculus ( ).

Although numerous studies have examined BD’s neurobiology, the majority of this work focused on patients with treatment-resistant depression has done so in the context of unipolar depression—not bipolar depression ( ). That being said, some of the studies that investigated interventions for TRBD (discussed in detail below) targeted a number of the biological mechanisms discussed above. Next, we will discuss important clinical issues concerning the management of TRBD more broadly. We will then summarize intervention studies for patients with TRBD, specifically, focusing on the results of randomized controlled trials that enrolled patients with rigorously-defined treatment-resistant illness.

Initial assessment

When a clinician is treating a patient with bipolar depression who has not had an adequate response to sequential trials, it is imperative to carefully reevaluate the diagnosis to, first, confirm the existing diagnosis of BD and, second, to investigate missed or inadequately-treated psychiatric and nonpsychiatric comorbidities, assess treatment adherence, investigate whether past treatments for BD have been delivered at proper doses and for sufficient periods of time, and to evaluate the quality of (and adherence to) psychosocial interventions ( ).

In a survey of individuals with BD, 48% of the respondents did not receive the diagnosis of BD until they had consulted with three or more professionals, and 10% received the diagnosis only after visiting with seven or more professionals ( ). These findings highlight the challenging nature of diagnosing BD, even in mental health specialty settings; therefore, the chance of misdiagnosis should always be considered when dealing with treatment-resistant patients. Efforts at clarifying the BP diagnosis may be enhanced by obtaining additional histories from family members and other collateral informants and by using structured or semistructured interviews ( ). BD is often confused with borderline personality disorder, given a number of shared clinical features such as impulsivity and emotional dysregulation ( ). In the study of , among 145 patients who had reported a diagnosis of BD, the diagnosis could not be confirmed in 56.5% of the sample after using a gold-standard structured interview. Both conditions are also highly comorbid, conferring an additional challenge in the management of the patients. A systematic review found that 21.6% of people with BD may also meet diagnostic criteria for borderline personality disorder and 18.5% of individuals with borderline personality disorder may beet diagnostic criteria for BD ( ). A high frequency of cooccurring substance abuse or dependence and anxiety disorders has also been reported in BD patients ( ). Regarding nonpsychiatric comorbidities in patients with BD, Forty et al. found a self-reported frequency of asthma, diabetes, dyslipidemia, and hypertension in patients with BD of 19.2%, 6%, 19.2%, and 15%, respectively. The degree of burden from comorbid general medical conditions have been associated with longer illness duration, a greater number of psychiatric admissions, worse functioning, and ECT treatment in patients with BD ( ).

BD is a chronic illness that usually requires a complex treatment approach, including distinct pharmacological interventions—each with different dosage, adverse effect, and efficacy profiles—and adjunctive psychological interventions. About one-third of BD patients in the United States are receiving polytherapy, with almost three psychotropic medications per person on average ( ). Thus, patients who present a lack of response to several treatments for bipolar depression need careful evaluation of current and past treatments, with an eye toward nonadherence, inadequately conducted therapeutic trials (due to inadequate treatment duration and suboptimal dose/blood levels where applicable), and the use of interventions not supported by the best scientific evidence available before classifying patients as having TRBD. reviewed adherence and pharmacological treatment profiles among patients with BD in the United States. The authors reported that only 30% of the patients remained on the prescribed mood stabilizer after 1 year of treatment. The results also showed an association between common comorbidities, such as a history of alcohol or drug abuse, and higher illness complexity (including moderate to severe BD, an indication of self-harm, or comorbidity other than substance abuse) with lower treatment adherence ( ). Low conformity with guidelines for treatment could also prevent patients from responding to evidence-based interventions, although some studies have shown no significant association between good compliance with guideline-based practices and clinical outcomes in young patients with BD ( ; ). On the other hand, showed that both suboptimal medication adherence and clinical management were among the main drivers of the direct economic costs of BD, which were estimated at around $50 billion in the United States.

Psychosocial interventions

Psychosocial interventions have a crucial role in the management of patients with BD. In a systematic review, Miklowitz et al. found that cognitive behavioral therapy (CBT), family or conjoint therapy, and interpersonal therapy were associated with stabilizing depressive symptoms. Also, the findings showed the benefits of psychoeducation with guided practice of illness management skills in a family or group format in preventing recurrences and a better retention profile of brief psychoeducation and family therapy ( ). Other advantages of psychosocial interventions to treat patients with BD include educating patients about their illness, addressing comorbid psychiatric disorders, promoting self-monitoring, managing stress, addressing problems with relationships and work, and developing a plan to cope with an acute crisis ( ). reviewed published studies that focused on the clinical effects of evidence-based, bipolar-specific psychotherapies including psychoeducation, CBT, functional remediation, family-focused psychotherapy, interpersonal and social rhythm therapy, and integrated care management. However, as the authors point out, most randomized controlled trials that compared two psychosocial interventions did not find considerable differences. This suggests that the psychosocial intervention of choice may depend on treatment availability and a continuous reassessment of psychosocial needs in consultation with the patient and their family members (if appropriate) ( ). Guideline-based recommendations for various psychosocial interventions as adjuncts to pharmacotherapy for acute bipolar depression and bipolar maintenance treatment were summarized by . The information provided highlighted the role of psychoeducation as a first line recommendation (Canadian Network for Mood and Anxiety Treatments (CANMAT)/International Society for Bipolar Disorders (ISBD) and British Association for Psychopharmacology) and level 1 evidence (Royal Australian and New Zealand College of Psychiatrists (RANZCP)) for bipolar maintenance and CBT as a second line (CANMAT/ISBD) and level 1 evidence (RANZCP) for acute bipolar depression ( ).

Pharmacological treatment

Rigorous pharmacological treatment is fundamental to the management of psychiatric symptoms in patients with BD. Bahji et al. reviewed randomized controlled trials for the treatment of bipolar depression and performed a network meta-analysis of 50 randomized trials (totaling 11,448 participants) to investigate the comparative efficacy and tolerability of pharmacological treatments. The network meta-analysis supported the efficacy of divalproex, olanzapine/fluoxetine, olanzapine, quetiapine, cariprazine, and lamotrigine for bipolar depression, compared to placebo. Sertraline, paroxetine, and lithium in monotherapy were not effective compared to placebo ( ). The negative result with lithium contrasts with a number of reports supporting lithium for treating bipolar depression and for reducing the risk of suicidal behavior. For instance, from a nationwide cohort study, found that lithium was associated with a significant decrease risk of suicide in patients with BD who had been hospitalized. Lithium discontinuation has also been associated with high risk of illness recurrence and risk of suicide ( ). These findings make the well-documented declines in the use of lithium for bipolar disorder management all-the-more troubling. Indeed, a 20-year observational study documenting the trends in the pharmacological treatment in patients with diagnosed BD showed a decreasing percentage of visits for BD that included prescription of lithium—from 30.4% to 17.6%. In comparison, there was an increase in second-generation antipsychotics prescriptions from 12.4% to 51.4% ( ).

The sequencing of medication therapy for bipolar depression is addressed by several practice guidelines ( ; ; ). Integration of pharmacotherapy with psychosocial treatment is usually considered optimal. First-line medication considerations often prioritize monotherapy with treatments supported by randomized trials (e.g., quetiapine, lurasidone), most of which enrolled people with bipolar I depression. If monotherapy is ineffective, augmentation with mood stabilizers such as lithium, divalproex, or lamotrigine is usually recommended. If monotherapy with a particular agent is intolerable or if the addition of mood stabilizers as augmenting agents is ineffective, switching is usually indicated. Next step treatment options supported by controlled evidence include switching to the alternative evidence-based monotherapy, olanzapine plus fluoxetine, divalproex (if not trialed already), or mood stabilizer combination therapy (e.g., lithium plus divalproex or lamotrigine). If these therapeutic options are ineffective or poorly tolerated, additional treatment options include alternative monotherapies (e.g., lamotrigine, lithium, carbamazepine, olanzapine, or cariprazine), other mood stabilizer combinations (e.g., lithium plus carbamazepine or lamotrigine if not already trialed), and combination therapy with olanzapine plus lithium or divalproex. As noted earlier, some patients may respond to combination therapy with lithium or divalproex plus an antidepressant such as a selective serotonin reuptake inhibitor (e.g., fluoxetine) or bupropion; or combination therapy with a second-generation antipsychotic (usually quetiapine, lurasidone, or olanzapine) plus an antidepressant. Therapeutic options for multidrug-resistant bipolar depression include ECT, as reviewed further below.

To address partial responses, once misdiagnosis, treatment nonadherence, drug-drug interactions, medication side effects, psychosocial stressors and/or substance abuse destabilizing patient’s clinical condition are ruled out, drug dosage optimization and/or add-on pharmacotherapy may be preferable before considering switch medication ( ). For patients on second-generation antipsychotics, augmentation with lamotrigine, lithium, or valproate are options unless the patient has a history of nonresponse with these medications ( ). The efficacy of lamotrigine as an add-on treatment on lithium was investigated in a multicenter, double-blind, placebo-controlled trial. The findings showed a benefit for lamotrigine compared to placebo ( ). A systematic review and meta-analysis of six randomized controlled trials of add-on modafinil, armodafinil, and lisdexamfetamine compared to placebo reported a significant association of these medications with remission. The psychostimulants and stimulant-like drugs were not associated with a significant increase in adverse effects or dropouts than placebo ( ).

There are surprisingly few evidence-based therapeutic options for depressed patients with bipolar II disorder despite how common bipolar II disorder is encountered in clinical settings and the predominance of depressive episodes or symptoms. Of the available options, quetiapine, lithium, and lamotrigine may be the best-supported ( ). The CANMAT and the International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorders include as adjunctive options for the treatment of bipolar II depression the following medications in combination with mood stabilizing drugs: bupropion (second-line recommendation, level 2 of evidence), agomelatine (third-line, level 4), eicosapentaenoic acid (third-line, level 4), ketamine (third-line, level 3), N -acetylcysteine (third-line, level 4), pramipexole (third-line, level 3), and T3/T4 thyroid hormones (third-line, level 4) ( ).

For breakthrough depressive episodes in patients who responded initially to treatment, a similar approach to partial responses is suggested, including the investigation of an inadequate dose of medication, poor adherence to pharmacotherapy and psychosocial therapies, drug-drug interactions that may contribute to lower medication effectiveness, the use of concomitant medications (e.g., antidepressants) that may destabilize mood, and potential changes in thyroid functioning induced or not by lithium therapy ( ).

The use of antidepressants to treat bipolar depression in its acute phase is controversial owing to limited efficacy in large clinical trials, risk of mood destabilization (particularly in people with bipolar I disorder), and the risk of polar mood switching ( ). Much ambiguity in the literature remains about the role of antidepressants in people with bipolar depression. Most experienced clinicians have encountered bipolar patients who require adjunctive antidepressants to achieve remission from depressive symptoms and prevent depressive relapses once well. Moreover, the risk of polar mood switching with antidepressants in people with bipolar disorders appears to be lower than what was once believed, especially when antidepressants are combined with mood stabilizing medications. Therefore, we avoid the use of antidepressants in BD patients in absence of concomitant mood stabilizing medications with antimanic effects such as conventional mood stabilizers (e.g., lithium, divalproex, carbamazepine) and thymoleptic atypical antipsychotic drugs.

Next, we will discuss interventional studies including investigational/nonstandard options for patients with TRBD, focusing on randomized controlled trials.

Pharmacological

Nonpharmacological

Potential biomarkers of treatment-response

Some studies have investigated treatment response biomarkers in patients with BD and treatment-resistant depression, which could help provide more personalized treatments. Edberg et al. found lower levels of monocyte chemoattractant protein-1 (MCP-1) among nonresponders to a combination between celecoxib and escitalopram, suggesting a better response to this treatment for patients with higher levels of MCP-1 ( ). Response to repeated ketamine administration (six intravenous infusions over 12 days) was associated with kynurenine pathway metabolites in the study of Zhou et al. that included patients with unipolar and bipolar depression with suicidality or history of failure to at least two antidepressant treatments ( ). The authors found higher serum concentrations of kynurenic acid and kynurenic acid/kynurenine ratio at 24 h associated with lower depressive symptoms at days 13 and 26 following the sixth infusion ( ). Response to ketamine treatment was also associated with markers of circadian timekeeping in patients with unipolar and bipolar treatment-resistant depression, providing clinical evidence for the association between ketamine’s efficacy and the circadian system ( ). Villaseñor et al. found differences in the mitochondrial β-oxidation of fatty acids between responders and nonresponders to ketamine in patients with TRBD ( ). Clark et al. evaluated the association between rostral anterior cingulate (rACC) glutamate/glutamine concentration and treatment response to DBS of the subcallosal cingulate in 16 patients with TRD, two of them with BD. The authors reported that lower baseline glutamate could predict both reduction in depressive symptoms and response to treatment at 6 months ( ). The investigation of biomarkers for treatment-response could guide personalized strategies, and the characterization of the neurobiology associated with treatment-resistant in patients with bipolar depression could help identify more homogeneous groups of patients; both approaches could optimize the identification of novel therapeutic targets and the efficacy of existing treatments.