Trees in the Forest of Depression

Major depressive disorder (MDD) is the leading cause of disability worldwide and the most common disorder psychiatrists treat.¹ It is perhaps no surprise that MDD is highly heterogeneous. As with most psychiatric disorders, MDD is diagnosed based on observable symptoms, and it is polythetic: No single observable phenomenon is an essential condition for the diagnosis. With 227 combinations of symptoms meeting criteria for the disorder, individuals with MDD may have few or no symptoms in common.²

These combinations are like clumps of trees that intermingle in a vast forest. The subtypes currently recognized by the DSM-5-TR (melancholic features, atypical features, anxious distress, psychotic features, catatonia, peripartum onset, and seasonal pattern³) have historical bases, but the extent to which each of these clumps represents a distinct pathophysiology or pattern of treatment response is controversial: One-third of individuals meeting the criteria for a subtype also meet the criteria for 1 or more other subtypes.⁴ Nevertheless, subtypes of depression can have valuable implications for treating patients living with MDD in addition to being an exciting frontier for research.

Melancholic Depression

In the 16th-century engraving Melancholia I by Albrecht Dürer (Figure), a muse-like figure sits in darkness, with unused tools and uncut blocks of stone scattered about. A vast body of water separates the figure from a beam of light and a rainbow. Joy and motivation are far away. In the DSM-5-TR, depression with melancholic features requires anhedonia or lack of mood reactivity³—that is, the person with depression feels no better with good news or other pleasurable stimuli, as if they were marooned like the muse or angel in the engraving. Insomnia (especially early-morning awakening), poor appetite, and psychomotor agitation or retardation are hallmark symptom clusters. Melancholic depression responds worse to a placebo—the affected person may be cut off from even this potentially therapeutic effect. It may be associated with lower odds of remission with selective serotonin reuptake inhibitors (SSRIs) than with tricyclic antidepressants (TCAs)⁵ and electroconvulsive therapy (ECT); however, research directly comparing SSRIs and other relatively newer antidepressants with TCAs and ECT is lacking. Individuals are more likely to have severe depression and psychotic features, with important implications for diagnostic questioning and treatment.

One of us recalls that a supervisor, when discussing a patient, once kindly pointed out that a major depressive episode was a major depressive episode whether it seemed to arise “out of the blue” or emerged with a life event: loss of a loved one, a fall from grace at work or in love, or a serious injury or life-altering medical diagnosis. Endogenous depression was framed by Emil Kraepelin in the late 19th and early 20th century as arising from biological rather than psychological causes, and it is represented by the with melancholic features specifier in the DSM. While not a major focus of our current diagnostic framework, recognizing the source of a major depressive episode as “out of the blue” or as a psychological response to a life event has implications for rapport with patients.

Atypical Depression

Subtypes are dynamic and shift boundaries with new evidence. Take the debate over atypical depression: The current DSM asks for mood reactivity as a necessary condition for the specifier,³ yet some have argued for the prominence of other features. One researcher showed there was a stronger association with “reversed vegetative symptoms”––overeating and oversleeping, in contrast to the poor appetite and insomnia associated with melancholic depression.⁶ Others have argued for an earlier age of onset and a chronic rather than remitting course as being what really make atypical depression atypical.⁷ Regardless, the subtype was recognized in the latter half of the 20th century with the observation that patients with depression with certain features responded especially well to monoamine oxidase (MAO) inhibitors, suggesting a distinct physiological process. Although MAO inhibitors are often eschewed for antidepressants with more benign adverse effect profiles, some researchers argue that MAO inhibitors should be considered earlier for cases of atypical depression, although head-to-head comparisons with relatively newer antidepressants are again lacking.

Perhaps the most compelling hypothesis about the pathophysiology of atypical depression involves the hypothalamo-pituitary-adrenal (HPA) axis, which is hyperactive in melancholic and psychotic depression. Conversely, atypical features are not associated with hypercortisolism, and there is some evidence that they may be associated with hypoactivity of the HPA axis, similar to post-traumatic stress disorder.⁸

Anxious Depression

The melancholic patient may lie awake all night and feel cut off from joy, while the patient with atypical depression may oversleep yet retain the ability to respond appropriately to good news and pleasurable events. What about the patient with depression who is paralyzed by worry, feels tense throughout the days and nights, and fears that something terrible may happen to them or loved ones out of proportion to the likelihood of any threat based in reality?

Severe anxiety has been associated with a higher suicide risk for patients with depression, with important implications in assessing safety. The presence of severe anxiety also decreases odds of treatment response and predicts a longer duration of depression,⁹ which may help with setting expectations for the patient and their loved ones.

Psychotic Depression

Several treatment guidelines recommend ECT and antipsychotic medications for the treatment of the acute and maintenance phases of psychotic depression, but the quest for a distinct pathophysiology is ongoing. Structural MRI studies have focused on gray matter volume, which may be decreased in certain brain regions in psychotic depression compared with nonpsychotic depression. ECT is known to increase gray matter volume in some regions, supporting the neuroplastic hypothesis for its mechanism of effect.¹⁰ For antipsychotics, there is general agreement in treatment guidelines for their use in the acute phase of psychotic depression; however, some researchers question their standard use for maintenance treatment.^11,12

Catatonic Depression

The DSM-5 removed catatonia as a subtype of schizophrenia, instead describing it as a feature of several conditions, including bipolar disorder as well as MDD.¹³ Meanwhile, in 2022, the ICD-11 formally adopted catatonia as its own entity.¹⁴ The most common disorder comorbid with catatonia is MDD, which may reflect the high prevalence of MDD rather than a direct link between the 2 phenomena. The difference in classification invites the question as to whether catatonia is pathophysiologically related to underlying or comorbid MDD.

Seasonal Depression

In most cases of seasonal depression, major depressive episodes recur predictably during the fall or winter and remit in the spring. Younger people are more likely to meet criteria for MDD with a winter-type seasonal pattern.³ The prevalence of the winter type increases with latitude, but small sample sizes and methodological differences hamper reviews of bright light therapy¹⁵; more research is needed. Bupropion can be an effective preventive treatment, although the risk of adverse effects (eg, headaches) must be weighed against the potential benefit.¹⁶

Peripartum Depression

Psychotic depression and peripartum depression each respond to their own distinct set of treatments, which argues for a distinct pathophysiology for these subtypes. Referring to the onset of a major depressive episode during pregnancy or within 4 weeks of delivery (postpartum depression), peripartum depression impacts 10% to 20% of women worldwide, and there is a good deal of interest in emerging treatments for this highly prevalent condition. The US Food and Drug Administration approval of brexanolone, a neuroactive steroid that modulates GABA-A receptors, for postpartum depression in 2019 was based on data from clinical trials that demonstrated a rapid improvement in depressive symptoms. Progress in identifying the mechanism of this effect and biomarkers for diagnosis holds promise for the enduring utility of this subtype of MDD.¹⁷

Inflammatory Depression

Another subtype of depression—recently proposed, not listed as a subtype of MDD in the DSM-5-TR—similarly holds promise for biomarkers and individualized treatments. The specific symptoms typifying inflammatory depression are anhedonia, amotivation, fatigue, psychomotor retardation, and disrupted sleep and appetite (especially hypersomnia and hyperphagia, those symptoms referred to as “reversed vegetative symptoms” in describing atypical depression). This clump of trees in the forest of depression is associated with elevated inflammatory markers, including C-reactive protein. The possibility that an inflammatory pathophysiology might yield to certain treatments would be a welcome advance: Patients with a history of nonresponse to antidepressants have increased levels of inflammatory biomarkers and below average responses to psychotherapy. Proposed treatment targets include reduced activation of the ventral striatum during reward anticipation and dopamine and glutamate signaling in subcortical neural networks more broadly.¹⁸

Concluding Thoughts

Subtypes of MDD are exciting frontiers that are generating treatments for some of the major depressive episodes that have been most difficult to treat. Recent successes in the treatment of peripartum depression and the emerging subtype of inflammatory depression are likely steps toward identifying biomarkers and more individualized treatments for patients with MDD. In the meantime, we have guidance from valuable research on the implications of the subtypes as we currently understand them. Recognizing subtypes of depression can signal the part of the forest of depression in which the patient is stranded and paths that may lead out.

Dr Nelson is an assistant professor and the associate director of the Mood Disorders Program in the Department of Psychiatry and Behavioral Sciences at Montefiore Medical Center and Albert Einstein College of Medicine.

Dr Schwartz is a professor and the deputy chairman of the Department of Psychiatry and Behavioral Sciences at Montefiore Medical Center and Albert Einstein College of Medicine.

References

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