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L6 Psych Med Severe depression and bipolar disorder

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aliasesL6 Psych Med Severe depression and bipolar disorder

16 min read

Overview

This lecture covers the two severe ends of the mood disorder spectrum: Bipolar Disorder and severe/melancholic Major Depressive Disorder (MDD). It works through the historical concept of mood disorders, the diagnostic classification and criteria distinguishing mania/hypomania from BP depression/MDD, bipolar epidemiology and recurrence, pathophysiology, risk factors and adverse outcomes, then acute and maintenance drug management of mania and bipolar depression (with supporting trial evidence), before turning to melancholic/psychotic depression: its features, epidemiology, biology and treatment.

Historical concept and classification

  • Aretaeus (1st century) first identified mania and melancholia as related states in the same patient.
  • Falret (19th century) described “folie circulaire” (circular madness).
  • Kraepelin (1899) coined “manic depressive insanity”, distinguishing it from dementia praecox.
  • Mood disorders can be classified along three axes:
    1. Mood elevation component: none, hypomania (m), mania (M).
    2. Mood lowering component: none, dysthymia (d), major depression (D).
    3. Duration/frequency of mood swings.
  • Combining axes 1 and 2 gives the diagnoses: dysthymia and cyclothymia (mild elevation + mild lowering), pure mania (elevation only), major depression (lowering only), BP-II (hypomania + major depression), BP-I (mania, with or without depression).
  • This lecture focuses on Bipolar Disorder and severe MDD.

Diagnostic criteria: BP depression/MDD vs mania/hypomania

Key: * = a criterion symptom for that category.

  • Number of symptoms required: BP depression/MDD at least five*; mania/hypomania at least four*.
  • Stem criterion (must be present): BP depression/MDD, low mood or loss of interest*; mania/hypomania, elevated or irritable mood*.
  • Weight/eating: increased or decreased* in depression; not a mania criterion.
  • Sleep: increased or decreased* in depression; decreased* in mania.
  • Psychomotor activity: increased or decreased* in depression; increased* in mania.
  • Energy: decreased* in depression; increased in mania.
  • Self-esteem: decreased* in depression; increased* in mania.
  • Concentration: decreased* in both.
  • Suicidality: present* in depression; may be present in mania.
  • Talking, thinking, goal-directed activity (overactivity), risky activity: decreased in depression; increased* in mania.
  • Psychotic symptoms: may be present in depression; often present in mania, absent in hypomania.
  • Duration: at least 2 weeks* for depression; at least 1 week* for mania, 4 days* for hypomania.
  • Functioning: impaired* in depression; much impaired in mania, little impaired or increased in hypomania.
  • Must not be attributable to substances, antidepressants, or medical disorders (both categories).
  • A patient needs just one episode of mania to receive a Bipolar Disorder diagnosis.

Bipolar Disorder epidemiology

  • Mean age of onset: BP-I 18 years, BP-II 22 years; peak onset range 18-34 years.
  • Gender ratio: M = F (contrasts with MDD, which is 1:2, M:F).
  • Lifetime prevalence: 1-2% (vs 15% for MDD).
  • No association with race, ethnicity, socioeconomic status, or rural/urban setting.
  • Familial risk of developing BP disorder: one BP parent/sibling 20%; two BP parents 60%; monozygotic twin with BP 75%.

Recurrence of Bipolar Disorder

  • Pre-lithium era: approximately 4 recurrences per 10 years, with the interval between episodes tending to shorten as the patient ages (“cycle acceleration”).
  • A lifelong recurrence study (Eur Arch Psych Clin Neurosci 2003, 253:236) found BP recurrence approximately 2x higher than for MDD.
  • Cohort data: BP-I (n=160, follow-up 32.3y) had 10 episodes total, 0.4 episodes/year; BP-II (n=60, follow-up 30.2y) had 10.5 episodes, 0.3 episodes/year; MDD (n=186, follow-up 24.3y) had 4 episodes, 0.2 episodes/year.

Pathophysiology

  • Cause is unknown overall, but there is high genetic loading.
  • Polygenic, with individual risk genes of modest effect size, including:
    • CACNA1C: alpha-1C subunit of the L-type voltage-gated Ca2+ channel.
    • TENM4: teneurin transmembrane protein gene, involved in neuronal connectivity during development.
    • NCAN: neurocan core protein gene.
  • These risk genes are also implicated in schizophrenia, though rare copy number variants are less implicated in bipolar disorder than in schizophrenia.
  • Neuroimaging: white matter abnormalities in BD vs controls, seen as reduced diffusibility (a biomarker of tissue integrity) across most major white matter tracts (Neuropsychopharmacol 2019, 44:2285-2293), with the greatest changes in the corpus callosum and the cingulum. Of the tracts studied, the corpus callosum showed the largest effect size.

Risk factors, precipitants and adverse outcomes

  • Environmental precipitants: stress/life events, absence of close relationships, altered schedules/shift work.
  • Medical precipitants: thyroid over- or under-activity, drugs (e.g. steroids, interferons), chronic illness, anaemia.
  • Psychological precipitants: self-image/personality, ruminative thinking, other DSM-V diagnoses (anxiety, substance abuse, personality disorders etc), loss events.
  • Adverse health/social associations of Bipolar Disorder:
    • 5-10 year delay between the first mood swing and diagnosis.
    • Premature death 8-9 years earlier than the non-BP population, driven by cardiovascular disease, diabetes, COPD and suicide.
    • Suicide risk 8-10x higher than baseline; 30-50% of BP patients attempt suicide, 15-20% complete suicide.
    • Forensic: high rates of incarceration, strongly associated with mania and comorbid disorders.
    • Associated with unemployment (30-50%), poverty and impaired functioning.

Overall treatment framework

  • Nondrug interventions: psychological/social management, hospitalisation.
  • Drug treatments: treatment of acute episodes (mania, BP depression) and prevention of mood episode recurrence (both depression and mania).

Psychological/social management

  • Education: about the disorder and its treatments, about stable lifestyle routines (e.g. sleep hygiene, anticipating and managing life stress), and about early warning signs of impending episodes with rescue medication strategies.
  • Case management: careful review of symptoms and side effects at each clinic visit, life charting of previous episodes, daily mood diary.
  • Social/psychological support and therapy: specific psychological therapies (CBT) and psychoeducation improve treatment adherence; self-help and support groups.

Management of acute mania

  • Hospitalisation may be necessary: low stimulus environment, boundary setting, supervised medication, prevention of suicide, and use of the Mental Health Act where required.
  • Drug therapy: a mood stabiliser (lithium or valproate) plus an antipsychotic (e.g. risperidone, olanzapine) and/or a benzodiazepine (e.g. diazepam, clonazepam). Neuroleptic/benzodiazepine doses are down-titrated as manic symptoms resolve, over 2-3 weeks.
  • Evidence for drug choice in acute mania:
    • Cipriani 2011 (Lancet), a Bayesian network meta-analysis of individual drugs (monotherapy and combination studies), ranked drugs on efficacy and acceptability; olanzapine, risperidone and haloperidol clustered in the best combined efficacy/acceptability region, while topiramate and gabapentin performed worst on both measures.
    • Glue & Herbison (ANZJP 2015, 49:1215), a network meta-analysis of 15,177 participants across 62 acute mania drug trials, found all drug options were more effective than placebo, and that combined antipsychotic + mood stabiliser therapy was more effective overall than either drug class alone. Probability of being the best treatment: combined antipsychotic/mood stabiliser was highest for mania score (96.1%), YMRS (85.5%) and responder outcome (99.3%), and had a lower dropout probability (17.8%) than antipsychotic monotherapy (82.0% dropout probability, the highest of any group).

Management of bipolar depression

  • Antidepressive effects of mood stabilisers: 80% of BP depressed patients show a partial or good response to lithium (J Clin Psychopharm 1993; 13:397-408), though onset of activity may take 6-8 weeks. Lithium plus an antidepressant is more effective than placebo plus an antidepressant (Psychopharm 1995, 118:223-225; Arch Gen Psych 1984, 41:1096-1104). There are fewer data for other mood stabilisers (valproate, lamotrigine) in BP depression.
  • Antidepressants should be used cautiously in BP depression: used alongside a mood stabiliser, and their benefit is difficult to demonstrate in RCTs.
    • Risk of antidepressants inducing mania may be up to 10%; risk factors are BP-I (more than BP-II), female sex, and a recent manic episode.
    • Risk of antidepressants inducing rapid cycling (4 or more mood cycles in 12 months).
  • ECT is used for refractory BP depression.
  • Ketamine in refractory bipolar depression (Diazgranados, Arch Gen Psych 2010): treatment-refractory, unmedicated bipolar depression (n=18), randomised double-blind two-period crossover trial, ketamine (0.5 mg/kg) vs placebo via 40-minute IV infusion, assessed to 14 days. Ketamine produced a sharp drop in MADRS score within 40-80 minutes that remained lower than placebo out to day 14, and a markedly higher MADRS responder rate (40-58%) than placebo (near 0%), though the ketamine response had declined to around 7% by day 14.

Bipolar maintenance therapy

  • Prophylaxis is indicated if a patient has had more than 2 manic or depressive episodes in 5 years.
  • Lithium is first choice:
    • Despite efficacy, recurrence still occurs (approximately 20% over 1 year, 76% over 5 years).
    • Adequate blood levels must be maintained, as recurrence is higher at lower concentrations.
    • Monitoring needed: weight, thyroid/parathyroid function, renal function.
    • Poor tolerability may reduce compliance.
  • Valproate, carbamazepine and lamotrigine have no obvious efficacy advantage over lithium and have fewer controlled data.
  • Quetiapine (an antipsychotic) can be used as monotherapy.
  • Polarity Index (Popovic D, Eur Neuropsychopharm 2012, 22:339): the ratio of NNT for prevention of mania relative to NNT for prevention of depression, from >24-week placebo-controlled RCTs. A value of 1 indicates similar relative efficacy for preventing mania and depression; below 1 indicates antidepressant-predominant efficacy; above 1 indicates antimanic-predominant efficacy. On this index, lurasidone and lamotrigine sit toward antidepressant predominance; lithium, olanzapine, quetiapine, asenapine, ziprasidone and aripiprazole sit near the middle; risperidone and paliperidone sit toward antimanic predominance.
  • BALANCE study (lithium vs valproate vs combination in BP-I maintenance, Lancet 2010, 375:385): BP-I patients randomised to lithium, valproate, or combination, primary endpoint new treatment-emergent mood episode. Hazard ratios (95% CI): combination vs valproate 0.59 (0.42-0.83); combination vs lithium 0.82 (0.58-1.17); lithium vs valproate 0.71 (0.51-1.00). Median survival time to new episode: combination 15.5 months (10.4-*), lithium 10.5 months (7.7-18.3), valproate 7.1 months (4.6-12.2). Conclusion: combined valproate/lithium and lithium monotherapy are both better for BP-I maintenance than valproate monotherapy alone.

Severe/melancholic and psychotic depression

  • Across the severity spectrum of MDD, psychological contribution to aetiology decreases and biological contribution increases with severity; melancholia/psychotic MDE sits at the severe end and is majority non-bipolar.
  • Melancholic depression features:
    1. Mood: intense, unremitting apprehension and morbid statements, blunted emotional response, nonreactive mood, pervasive anhedonia.
    2. Psychomotor disturbance: either retardation (slowed thought, movement, speech, anergia) or agitation (motor restlessness).
    3. Cognitive impairment: decreased concentration and memory.
    4. Vegetative dysfunction: interrupted sleep, decreased appetite/weight, diurnal variation (generally worse in the morning).
    5. Psychosis is often present, with common themes of nihilistic delusions of hopelessness, guilt, sin, ruin, or disease.
  • Characteristics of depressive psychosis:
    • Mood-congruent delusions (poverty, death, guilt etc).
    • Mood-congruent hallucinations in approximately 50% of cases: auditory (dead ancestors calling out), olfactory (smelling one’s own body decaying), tactile (feeling one’s intestines falling out because of rotting body parts).
    • Cotard’s syndrome (delusion of being dead or non-existent) can occur.
  • Epidemiology of melancholia/psychotic depression: approximately 5% of all MDD cases; M = F; likelihood increases with age, especially over 45 years; possibly associated with earlier age of onset of MDD, more suicide attempts, and greater chronicity and functional impairment.
  • Biology: hypercortisolaemia; sleep EEG changes, including reduced latency to the first REM period.
  • Treatment of melancholia/psychotic depression:
    • Hospitalisation plus Mental Health Act use where needed, given high risk of suicide and severe self-neglect, and risk of starvation/dehydration.
    • Antidepressant plus antipsychotic combination.
    • ECT.
    • Very low response rates to placebo or psychotherapy alone.

Summary

  • Bipolar Disorder, melancholia and psychotic MDE are all relatively uncommon presentations.
  • Onset of Bipolar Disorder is in early adulthood; melancholia/psychotic depression tends to occur later in life.
  • Both mood disorder groups tend to be recurrent, with a high probability of recurrence, greater for bipolar disorder than for major depression.
  • Effective acute and maintenance treatments exist, spanning psychological, social and pharmacological approaches.
  • Early recognition and treatment is essential to reduce morbidity/mortality and to improve functioning.

Self-test

  1. Describe the three axes used to classify mood disorder diagnoses on the mood elevation/mood lowering spectrum, and give the diagnosis produced by combining mild elevation with severe lowering.
  2. List the DSM-style stem criterion and minimum symptom count required for a diagnosis of mania/hypomania versus BP depression/MDD.
  3. What is the minimum duration required to diagnose mania, hypomania, and a major depressive episode respectively?
  4. How many manic episodes are required for a patient to receive a diagnosis of Bipolar Disorder?
  5. Compare the mean age of onset, gender ratio and lifetime prevalence of Bipolar Disorder with those of MDD.
  6. What is the risk of developing Bipolar Disorder in a person with one affected parent/sibling, two affected parents, and a monozygotic twin with BP disorder respectively?
  7. Explain how recurrence rate and episode frequency differ between BP-I, BP-II and MDD, citing the cohort data given.
  8. Name three genes implicated in the polygenic risk for Bipolar Disorder and state what each encodes or its proposed role.
  9. What white matter finding characterises Bipolar Disorder on diffusion imaging, and which tracts are most affected?
  10. List the adverse health and social associations of Bipolar Disorder, including the suicide attempt and completion rates.
  11. Describe first-line drug management of acute mania, including the down-titration strategy.
  12. According to the Glue & Herbison 2015 network meta-analysis, which treatment strategy had the highest probability of being the best treatment for mania score, YMRS and responder outcome, and how did its dropout risk compare with antipsychotic monotherapy?
  13. What proportion of BP depressed patients respond to lithium alone, and what is a key caveat about its onset of action?
  14. What are the risks of using antidepressants in bipolar depression, and which patient factors raise the risk of antidepressant-induced mania?
  15. Describe the design and key result of the ketamine trial in refractory bipolar depression.
  16. When is prophylactic maintenance therapy indicated in Bipolar Disorder, and what monitoring is required for a patient maintained on lithium?
  17. Explain what the Polarity Index measures and where lithium and lamotrigine fall on it.
  18. Summarise the BALANCE study design and its main finding regarding lithium, valproate and combination therapy for BP-I maintenance.
  19. List the five feature domains of melancholic depression with one defining detail for each.
  20. Describe three sensory modalities in which mood-congruent hallucinations can occur in depressive psychosis, with an example theme for each.
  21. What is Cotard’s syndrome?
  22. Outline the treatment approach for melancholic/psychotic depression.
  23. A 50-year-old patient presents with unremitting low mood, psychomotor retardation, marked weight loss, and the belief that her internal organs have rotted away. Which severe depressive subtype does this suggest, and what is the immediate management priority?
  24. Contrast the typical age of onset and biological versus psychological aetiological weighting between Bipolar Disorder and melancholic/psychotic depression, and explain why this distinction matters for how each is treated.

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