The clinical relevance of qualitatively distinct subtypes of depression
Authors: Lars Vedel Kessing, Jens Drachmann Bukh
Journal: World Psychiatry (2017)

Depression is a heterogeneous disorder, with great variation in symptoms and behavior, severity, onset and course. Given its broad nature, it is likely that diverse aetiologic and pathogenetic factors are involved in different subtypes of the disorder. Despite encouraging research findings, including genetics, epigenetics, gene expression, combinations of biomarkers in peripheral blood, neurocognition, and neuroimaging, biomarker candidates for depression remain still not useful in clinical practice. Furthermore, aetiologic and pathogenetic factors are rarely studied in subtypes of depression. Clinically, subtypes of depression are to some degree qualitatively distinct and of some relevance in predicting prognosis and treatment outcome. Different subtypes of depression can be identified according to polarity (unipolar vs. bipolar), symptoms (melancholic, atypical, psychotic, or anxious), onset (specific events, seasons, or age), recurrence, and severity1. These diagnostic specifiers and subgroups may guide treatment decisions to some extent. Most clearly, the distinction between unipolar and bipolar depression, the latter being characterized by decreased psychomotor activity2, implies different treatment options. Antidepressants are used as first-line monotherapy in unipolar but not in bipolar depression1, as in the latter they may induce switch into mania or mixed episodes, destabilize mood and potentially increase the risk of developing rapid cycling. Further, the distinction between mild, moderate and severe depression predicts the long-term risk of relapse and suicide3 and guides to some extent the choice of treatment (e.g., mild depression should not be treated with antidepressants, as long as the depressive episode does not get a chronic course). There is some evidence that tricyclics (TCAs) and electroconvulsive therapy are more effective in melancholic depression than selective serotonin reuptake inhibitors (SSRIs) and psychotherapy, and that monoamine oxidase inhibitors are more effective in atypical depression, although this evidence is still controversial. Psychotic depression often requires treatment with a combination of antidepressants and antipsychotics, and light therapy has effect in seasonal depression. Finally, compared with late-onset depression (31-70 years), early-onset depression (18-30 years) may present with more comorbid personality disorders and neuroticism, and fewer stressful life events prior to onset, but treatment response has not been found to differ between these groups4. Beyond these partly controversial clinical and treatment implications, subtyping of depression remains to be investigated in much more detail. A so far widely overlooked complication in the above studies is that the pathophysiology and psychopathology of depressive episodes may change during the course of illness, due to the progressive nature of unipolar disorder, with increasing risk of recurrence, duration and severity of episodes5. Consequently, a staging model has been suggested in unipolar depression, with a prodromal stage with vague symptoms and subthreshold mood symptoms progressing to a single depressive episode, recurrent depression and ultimately treatment resistance6. Nevertheless, there is at present no clear evidence that treatment response decreases with the number of episodes6. A more psychopathological and poorly studied approach is to characterize subtypes according to the presence of the core features of depression, i.e., symptoms that are required to fulfill DSM and ICD operational criteria. According to the DSM-5, the core features of depression are depressed mood and anhedonia. ICD-10 adds a third core item, "decreased energy or increased fatigue". These core features have been identified clinically to be central to depression and are included in the six-item version of the Hamilton Depression Rating Scale, along with guilt feelings, psychic anxiety and psychomotor retardation7. This scale is clinically and psychometrically valid, but does not characterize phenomenologically the three core features. These features may also identify three subtypes of depression, marked predominantly by depressed mood, anhedonia or decreased energy/increased fatigue, respectively. However, such potential subtypes of depression have been studied rarely, partly due to the fact that the core items of depression have not been clearly operationalized. The ICD-10 Diagnostic Criteria for Research state that depressed mood should be "to a degree that is definitely abnormal for the individual, present for most of the day and almost every day, largely uninfluenced by circumstances (non-reactivity), and sustained for at least 2 weeks". This wording is partly replicated in the ICD-10 itself: "The lowered mood varies little from day to day, and is often unresponsive to circumstances, yet may show a characteristic diurnal variation". The DSM-5 requires depressed mood to be present "most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others". Anhedonia has also been seldom studied, partly due to its inconsistent conceptualization in depression8. Aspects of anhedonia (e.g., low interest-activity), have been found to predict poor antidepressant outcome and prolonged time to remission8. Analogously, although psychomotor disturbances may have prognostic implications, explicit definitions of psychomotor phenomena remain elusive9. We are currently developing and testing the applicability of a new diagnostic assessment of depression, which focuses on the phenomenology of the core features of the syndrome according to ICD-10 and DSM-5 (depressed mood, anhedonia, and decreased energy), the CORE Interview. We propose that an increased emphasis on the phenomenology of the core items will improve the validity of the diagnosis of depression and help to identify clinically meaningful subtypes. A more specific diagnosis can help clinicians identify the patients who are more likely to benefit from certain types of antidepressant treatment and improve the search for genes and biomarkers for mood disorders. Lars Vedel Kessing, Jens Drachmann Bukh Psychiatric Center Copenhagen, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark