| Background: depression in bipolar disorder |
Debate over Kraepelin’s inclusive concept of manic-depressive illness (MDD) continued until 1980 with a first formal separation of bipolar disorder (BD) with mania from non-bipolar major depressive disorder (MDD) in the DSM-III.
The discussion continues between grouping mood syndromes and separating various depressive and bipolar subtypes, considering a "spectrum" of disorders ranging from more or less pure depression to archetypal BD, leading to profound therapeutic ambiguities.
Timely diagnosis and effective short- and long-term treatment of depressive episodes in patients with BD are of critical importance. Bipolar depression (BD) is associated with general morbidity, coexistence with other psychiatric conditions, disability, and excess mortality due largely to suicide.
Clinical challenges include the often delayed diagnostic differentiation of depression as the initial presentation of BD with non-bipolar MDD, more so after juvenile onset. Depression is initially considered unipolar MDD in up to 40% of patients subsequently diagnosed with TB.
Patients with BD may not recognize moderate increases in mood, energy, activity, or libido as clinically relevant hypomanic symptoms. Diagnostic uncertainty is especially likely early in the disease course; In 12-17% of cases, BD is not recognized until there is a spontaneous mood "switch" to hypomania or mania ("[Hypo]mania") or upon exposure to a mood-enhancing substance.
Other indirect factors that suggest a TB diagnosis include:
(a) familial mania, psychosis, nervous breakdown, or psychiatric hospitalization;
(b) early onset of illness, commonly with depression
(c) cyclothymic temperament
(d) multiple recurrences (≥ 4 depressive episodes within 10 years)
(e) depression with prominent agitation, anger, insomnia, irritability, talkativeness, others mixed or hypomanic features or psychotic symptoms
(f) clinical worsening, especially with mixed features during antidepressant treatment;
(g) suicidal ideation and acts
(h) substance abuse.
The total time of the depressive phases of BD and the duration of depressive episodes are much longer than in [hypo]mania, with surprisingly high morbidity in BD despite effective treatment.
| Morbidity and disability |
The high proportion of time with depression in patients with TB is associated with dysfunction and disability, decreased academic achievement and work success.
Common psychiatric conditions in BD include substance abuse and anxiety disorders, as well as personality and behavioral disorders. These diagnoses may contribute to the complexity and possible inconsistency of therapeutic options, compromising clinical care.
Patients with TB are also at increased risk for other general disorders that increase morbidity.
Cardiovascular diseases are particularly common, where factors prevalent in TB such as obesity, inactivity, diabetes, metabolic syndrome and increased inflammatory factors mediate. With TB, life expectancy is reduced by 12 to 15 years, contributing to substance abuse, smoking, overweight, limited access to adequate medical care and, in particular, depression.
| Bipolar depression and suicide |
The standardized mortality rate (SMR) for suicide in BD is ~ 20. Suicide risk is classified according to diagnosis: BD-I = BD-II, especially with mixed or psychotic features ≥ severe MDD with hospitalization > moderate depression in outpatients.
The risk of suicide is especially high following a psychiatric hospitalization, in association with delay or lack of adequate aftercare.
Among patients with TB-I and TB-II, especially with mixed or psychotic features, the risk of suicide is among the highest of all psychiatric disorders despite supposedly effective treatments. This disparity almost certainly reflects the great difficulty of treating depressive and mixed states in BD, added to the notably long delay in recognition of the condition.
Suicide cannot be “treated” but it can be prevented. Research on treatments aimed at suicide prevention is very limited due to the clinical and ethical issues that arise if an inactive or ineffective treatment, such as placebo, is compared to an experimental intervention, with death as a potential outcome.
The rarity of suicide, even among psychiatric patients, encourages research’s reliance on more prevalent measures such as suicidal ideation, self-injurious acts, or emergency interventions. Treatments for BD with potential suicide prevention include antidepressants, anticonvulsants and lithium, antipsychotics, electroconvulsive treatment (ECT), and psychosocial interventions.
• Treatment with antidepressants : The strong association of suicidal behavior with depression suggests that treatment with antidepressants could reduce the risk of suicide, although most studies have provided inconsistent evidence. Furthermore, the risk of clinical worsening, as well as the possibility that depression is the initial episode of BD, must be considered at any age, especially early in treatment.
• Lithium treatment: A reduced risk of suicide attempt during long-term treatment with lithium is shared by most studies, so several expert reports recommend it to limit the risk of suicidal behavior in patients with TB.
• Anticonvulsant treatment: Few studies directly compared suicide risks during anticonvulsant treatment, with findings largely inconsistent and inconclusive.
• Treatment with antipsychotics: The effects of these drugs remain poorly evaluated in relation to suicidal behavior. Clozapine has not been adequately evaluated in patients with TB, although it may have antimanic or mood-stabilizing effects.
• Other treatments: There is increasing evidence that ketamine can exert a rapid, short-term reduction in suicidal ideation along with a rapid reduction in symptoms of depression, even in patients with TB, although with uncertain effects and some concern of that its suspension causes adverse clinical responses. ECT appears to help in suicidal emergencies, but lacks evidence of sustained effectiveness. Additional interventions of potential value include emergency hospitalization and psychotherapy, particularly cognitive-behavioral, dialectical, and interpersonal methods, which may improve depressive symptoms and reduce suicide risk.
| Bipolar depression treatment |
As noted, depressive, dysthymic, and mixed states account for the majority of the disease burden in BD. Surprisingly few treatments have been shown to be consistently effective for acute episodes of bipolar depression, and there is even less evidence supporting long-term protection against recurrences. The lack of highly effective treatments encourages the widespread use of drug combinations and other treatments that are not approved or tested for efficacy and safety.
• Antidepressants: The ease and relative safety of treating depressive episodes with modern antidepressants, and efforts to minimize or avoid depression by physicians and patients, have made these drugs the primary treatment for BD. However, there is a surprising paucity of research and inconsistent findings, with particularly serious gaps regarding dysthymia and dysphoria, mixed features, and long-term prophylaxis of bipolar depression. Many experts recommend caution when using
antidepressants, particularly in patients with TB-I, to avoid potentially dangerous mood swings, and encourage their use, if necessary, only with mood-stabilizing agents or SGAs, provided there is no current agitation or mixed features.
Despite the limited body of research, it is widely assumed that antidepressants may be appropriate for some patients with TB, and especially safe for TB-II depression. Selection of candidates for antidepressant treatment may usefully be guided by beneficial and well-tolerated responses, less severe non-rapid cycling illness, few depressive episodes, lack of change from depression to mania or current agitation, or even minor mixed characteristics.
There is widespread concern that antidepressant treatment for BD causes dangerous agitation or mania, especially in BD-I. This risk is more associated with the BD progression pattern of depression followed by mania before a stable interval ("DME") than with the opposite ("MDE"). The clinical consensus is that short-acting agents should be administered in BD, in moderate doses, slowly increased, and with effective co-treatment to stabilize mood, while monitoring for the possibility of emerging hypomania.
• Mood stabilizers: Several anticonvulsants have been used for BD, based on strong evidence of their short-term antimanic effects (carbamazepine and valproate) or long-term reduction in the risk of depressive recurrences (lamotrigine).
Despite lithium’s use as a treatment for BD for decades, it remains virtually unevaluated for acute bipolar depression. It has some long-term effectiveness against recurrences of bipolar depression as well as greater prophylactic effects against [hypo]mania, and benefits in mixed episodes of BD. Additionally, it can substantially reduce the risk of suicide in TB patients.
• Second-generation antipsychotics: SGAs, including cariprazine, lurasidone, olanzapine-fluoxetine, and quetiapine, are currently the only ones approved for the short-term treatment of acute depressive episodes in BD. Most responses in acute bipolar depression have been modest, and potential long-term protective effects require further study.
At effective doses, SGAs can cause adverse effects including excessive sedation, akathisia, weight gain, type 2 diabetes and other features of the metabolic syndrome (hyperlipidemia, hypertension), and rarely tardive dyskinesia. These adverse effects tend to limit the potential value of SGAs for the prophylactic treatment of DB recurrences.
• Other treatments: A growing number of pharmacological treatments for depression are under investigation, some with value in BD, such as the NMDA-glutamate receptor antagonist ketamine and similar agents (eg, apimostinel, rapastinel) . Neurosteroids that interact with GABAA receptors (e.g. brexanolone) may be of interest for DB. Agents of less certainty of value include polyunsaturated fatty acids, anti-inflammatories and probiotics.
Among non-pharmacological treatments, acute bipolar depression usually responds to ECT. Intense light therapy and sleep deprivation require adequate testing in TB. Vagal nerve stimulation (VNS) is approved by the FDA for treatment-resistant depression, with evidence of efficacy in BD and MDD, although with some risk of inducing mania.
Repeated transcranial magnetic stimulation (rEMT) and various forms of electrical brain stimulation remain experimental for DB. Finally, several replicable, manual-based forms of psychotherapy, alone or in conjunction with antidepressants, have shown promise for the treatment of patients with BD.
Conclusions
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