The burden of severe depression: A review of diagnostic challenges and treatment alternatives

Charles B. Nemeroff

Research output: Contribution to journalReview articlepeer-review

237 Scopus citations


Among the factors making recognition of severe depression problematic for clinicians are the heterogeneous nature of the condition, lack of standardized definitions, and concomitant comorbidities that confound differential diagnosis of symptoms. The spectrum of severity in depressive disorders is extraordinarily broad, and severity assessment is comprised of several metrics including symptom intensity, diagnostic subtypes, suicidality risk, and hospitalization status. The overall diagnosis is achieved through consideration of symptom types and severities together with the degree of functional impairment as assessed by the psychiatric interview. It is likely that no single fundamental neurobiological defect underlies severe depression. The chronicity and heterogeneity of this disorder lead to frequent clinic visits and a longer course of treatment; therefore, successful approaches may require an arsenal of treatments with numerous mechanisms of action. The categories of drugs used to treat severe depression are detailed herein, as are several non-pharmacologic options including a number of experimental treatments. Pharmacotherapies include tricyclic antidepressants, selective serotonin reuptake inhibitors, atypical antidepressants such as serotonin-norepinephrine reuptake inhibitors and monoamine oxidase inhibitors, and combination and augmentation therapies. Drugs within each class are not equivalent, and efficacy may vary with symptom severity. Patient adherence makes tolerability another critical consideration in antidepressant choice. The role of non-pharmacological treatments such as electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, and deep brain stimulation remain active avenues of investigation. Improved knowledge and treatment approaches for severe depression are necessary to facilitate remission, the ideal treatment goal.

Original languageEnglish (US)
Pages (from-to)189-206
Number of pages18
JournalJournal of Psychiatric Research
Issue number3-4
StatePublished - Apr 2007
Externally publishedYes


  • Electroconvulsive therapy
  • Selective serotonin reuptake inhibitor
  • Serotonin norepinephrine reuptake inhibitor
  • Severe depression
  • Transcranial magnetic stimulation
  • Tricyclic antidepressant
  • Vagus nerve stimulation

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry
  • Psychology(all)


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