Stratified therapy for bipolar disorder.

Stratification of patients and treatment phases is an important method to treat patients with bipolar disorder quickly and effectively. The relatively low response rates and long treatment adjustment periods suggest that the potential for treatment stratification is particularly high in bipolar disorder. In the future, biomarkers will help to significantly improve psychiatric diagnostics. The potential of the clinical psychiatric examination is often underestimated. History and clinical examination provide important clues for choosing the best treatment.

An important goal of medical diagnostics is to predict response to treatments. At best, the diagnosis allows treatment to be tailored to specific disease processes. Current psychiatric diagnosis, which is not based on causes and pathophysiology but is oriented solely on relatively nonspecific symptoms, exploits the potential of clinical investigations only to a limited extent. The often long trial-and-error phases in therapy adjustment and the increasing use of complex combination treatments are probably an expression of this problem. Psychiatric research is therefore making great efforts to develop tests that allow specific disease processes to be identified in mental disorders, so that specific treatments can be developed and tailored to them. The term “personalized medicine” often used in this context is rather misleading, as it is not possible for statistical reasons to tailor therapies to a single individual on the basis of scientific evidence.

Therefore, the development of improved clinical investigation methods and biomarkers will not lead to person-specific treatments, but to new or improved classification of mental disorders. In addition to the term “stratified medicine,” the term “precision medicine” captures this development in medical research relatively well.

Why stratified treatment for bipolar disorder?

There is a body of evidence that symptom-based diagnosis is particularly inaccurate in bipolar disorder. For example, international treatment guidelines for common mental illnesses such as unipolar depression or schizophrenia are much more uniform than those for bipolar disorder, which are strikingly inconsistent. In particular, there are substantial differences between recently published national and international treatment guidelines for bipolar depression [1]. These differences are not subtle but involve fundamental decisions, such as whether to treat bipolar depression primarily with monotherapy or with combination therapy. Recommendations on the use of lithium, lamotrigine, and antidepressants vary widely. Not even quetiapine, which has a relatively good evidence of efficacy, is recommended as first-line treatment by all guidelines.

These discrepancies reflect the low average response rates of antidepressant monotherapies and the frequent need for combination therapies, which are poorly studied scientifically. Furthermore, available methods to predict adverse drug reactions (ADRs) in bipolar disorder are insufficient.

The underestimated potential of the clinical examination

The strong focus of psychiatric research on genetics and neurobiology has been accompanied by a neglect of clinical research methods. The justified concern about the reliability of psychiatric diagnoses has led to deficits in clinical validity: Psychiatric examination in clinical trials has increasingly degenerated into counting symptoms. It should not be forgotten that the essential difference between severe psychotic bipolar disorder and schizophrenia – if there is such an essential difference at all – is not primarily the clinical symptoms, but the course of the disease with the typical drop in cognitive performance in schizophrenia and the absence of this “kink” in bipolar disorder.

Furthermore, the strongest available predictor of treatment success in bipolar disorder is not a symptom, nor a gene, nor a biomarker, but history: anamnestic prior response to treatment and/or evidence of effective treatment in family members. Such crucial clinical factors are rarely considered in large, controlled therapeutic trials.

Regarding the underestimated potential of clinical psychiatric assessment, reference should be made to the recent review by Fava GA, et al. referred [2].

Improvement of diagnostic criteria in DSM-5

The DSM-5 provides the following changes to the diagnostic criteria:

Bipolar disorders are no longer part of the “Mood Disorders” category, but form their own “Bipolar and Related Disorders” category.
Mixed episodes should be abandoned in favor of a “mixed features specifier” that can be applied to depressive, hypomanic, and manic episodes.
Full manic episodes occurring on antidepressant therapy are considered sufficient for a diagnosis of mania.
Anxious Distress Specifier can be used to diagnose anxiety symptoms that often occur in bipolar disorder.

With respect to stratified therapy, the introduction of a “mixed features specifier” is particularly important because mixed episodes are especially resistant to therapy and there is evidence that mixed episodes respond particularly well to the atypical antipsychotics asenapine and olanzapine [3].
Bipolar patients with prominent anxiety symptoms are more likely to have a chronic course, increased risk for alcohol and drug dependence, and increased risk for suicide. Additional treatment with benzodiazepines may be useful.

Acute treatment of mania

The classic way of stratifying treatment in bipolar disorder is not by person characteristics, but by clinical phase. When manic episodes occur, antimanic medication should be optimized and antidepressant medication should be reduced or discontinued.

Meta-analyses [4] demonstrate good anti-manic efficacy for risperidone, olanzapine, haloperidol, aripirazole, quetiapine, lithium, and valproate. Olanzapine, quetiapine, and lithium have the advantage of having a good relapse prophylactic effect, thus avoiding a change of medication after the mania has subsided. Risperidone and aripirazole have the advantage of providing a depot injection for drug relapse prophylaxis. Asenapine is approved in Switzerland as an antimanic agent (additionally approved for schizophrenia in the U.S. and Australia). In terms of efficacy, it is comparable to olanzapine; in terms of risk for the development of metabolic syndrome, it is superior to olanzapine. Asenapine is also particularly suitable for use in emergency situations because it is absorbed orally and has a rapid onset of action. In agitated mania, loxapine administered with an inhaler shows a particularly good sedative effect [5]. However, this drug has not yet been registered in Switzerland. The combination of an atypical antipsychotic with lithium or valproate is probably the most effective anti-manic pharmacotherapy, although it should be noted that the likelihood of adverse effects is higher with combination treatments than with monotherapies.

Acute treatment of bipolar depression

Data regarding the treatment of bipolar depression are relatively inconsistent, indicating that more research is needed in this area.
In the United States, quetiapine, the combination treatment with olanzapine/fluoxetine, and lurasidone are approved for the treatment of bipolar depression. The Swiss Society for Bipolar Disorders recommends [6] quetiapine or quetiapine XR (dosage: 300-600 mg) [7] and lithium as first-line therapy in the treatment of depressive episodes in bipolar I disorder. The atypical antipsychotic lurasidone, approved in Switzerland for schizophrenia (in the United States for schizophrenia and bipolar depression), showed excellent efficacy in bipolar I depression in several studies as monotherapy or in combination with a mood stabilizer [8,9]. If monotherapy is insufficiently effective, the majority of treatment guidelines recommend combining it with an antidepressant. Lamotrigine is thought to be effective only in major depressive episodes.

Maintenance therapy and relapse prophylaxis

Long-term medication is a core component of maintenance therapy and relapse prophylaxis, the goal of which is to achieve a balanced mood. The best evidence of efficacy exists for lithium, which prevents manic and depressive episodes and has antisuicidal effects. The lithium effect is particularly pronounced in typical courses with clearly delineated manic and depressive episodes. Valproate is considered an alternative first-line treatment, especially for atypical courses, although the potential teratogenicity of valproate must be considered.

The great importance of maintenance therapy and relapse prophylaxis in bipolar disorders results from the fact that the potency of drug prophylaxis is significantly greater than that of drug acute therapy. This difference is consistent with the clinical observation that in acute relapse after discontinuation of lithium prophylaxis, the lithium effect is relatively small. This is not a problem specific to lithium and occurs with all prophylactic medications. Therefore, the indication for discontinuation of drug prophylaxis should be made cautiously and with the greatest care.

The concept of predominant polarity

The research group led by Eduardo Vieta in Barcelona has investigated and refined the concept of predominant polarity in several studies [10].
It is based on clinical naturalistic observation and states that in terms of long-term stabilization of bipolar disorder, there are three groups of
gives:

Bipolar patients who suffered predominantly from depressive episodes and symptoms benefited most, on average, from lamotrigine and/or quetiapine.
Patients who had predominantly hypomanic and manic episodes and symptoms were best stabilized with olanzapine, risperidone, clozapine, lithium, and/or valproic acid.
In patients with bipolar II disorders, antidepressants played an important role in long-term stability.

Although these findings are not results from controlled trials, they are of practical clinical relevance.

Suicide risk

Increased suicide risk is an important clinical feature for stratifying treatment for bipolar patients. Suicidal acts occur predominantly in depressive or mixed episodes. Successful treatment indirectly reduces the risk of suicide.

Lithium additionally has a strong direct antisuicidal effect, reducing the probability of suicide in affective disorders by 80% [11]. This effect exists independently of the mood-stabilizing effect and is probably due to the inhibition of aggressive impulses. Lithium reduces not only the frequency but also the lethality of suicide attempts.

Disease stage

Presumably, the stage of disease plays a much more important role in the choice of treatment than previously thought. In affective disorders, risk factors can change dramatically during the course. While psychosocial stress factors are among the most important risk factors in the early phases, their importance decreases in the course of the disease and “endogenous” neurobiological factors become more and more important. This is an important argument for detecting bipolar disorder early with the goal of achieving complete remission through effective treatment.

The importance of disease stage has been explored, particularly for psychosocial therapies. In the earlier stages, psychoeducation and classical psychotherapies are particularly effective. For patients with long, chronic courses, psychotherapies that specifically improve cognitive skills appear to be an important option [12].
Involving relatives is an extremely effective therapeutic measure in all phases of the disease.

Biomarker

To date, biological testing has failed to improve clinical practice. However, there are a number of promising findings. Patients with white matter hyperintensities and other neurotrophic changes appear to respond particularly well to lithium. High activity in the ventromedial prefrontal cortex predicted good response to antidepressants and deep brain stimulation in pilot studies. Generally reduced brain activity may indicate clinical or subclinical hypothyroidism and predict a good response to thyroid hormone augmentation. Furthermore, there is preliminary evidence that polymorphisms of specific genes are associated with the effects of psychotropic drugs: XBP1 gene -> valproic acid; BDNF gene -> Ltihium; 5-HTTLPR -> SSRI co-medication.

Prof. Dr. med. Gregor Hasler

Literature:

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Fava GA, et al: The Missing Link between Clinical States and Biomarkers in Mental Disorders. Psychother Psychosom 2014; 83: 136-141.
Ouanes S, Chennoufi L, Cheour M: An update on the treatment of mixed bipolar states: what is new in 2013? J Affect Disord 2014; 158: 53-55.
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