Approach To Mood Disturbances

Mood (Latin: modus = manner, way) refers to a pervasive and sustained emotional state that colours a person's perception of the world. Think of it as the "background music" of your mental life — it sets the tone for everything else.

Mood disorders are abnormal mood states with other associated features resulting in distress and functional impairment. ^[1]

A few critical distinctions right at the start:

Normal fluctuation vs. Abnormal state — an abnormal state refers to a pervasively high or low mood that differs from the usual mood. ^[1]

Mood fluctuations in response to disappointment, frustration, and losses in everyday life are usually short-lived. Natural despondency can have important survival function, resulting in reorientation and maturation. ^[2]

So sadness after a breakup, grief after a bereavement — these are adaptive. Depression as a disorder is different because:

1. Severity of symptoms is marked — e.g., DSM-5 requires "marked" diminished interest or pleasure, "significant" weight loss or gain ^[2]
2. It impairs adaptations and is often disabling ^[2]
3. When enduring, depression can result in impaired function at work, at school, and in the family ^[2]

WHO estimates 5% of adults suffer from depressive disorder worldwide, approximately 280 million people. ^[2]

The International Consortium of Psychiatric Epidemiology (89,037 adults from 18 countries) using the Composite International Diagnostic Interview found: ^[2]

• Average lifetime prevalence: 14.6% (high-income countries) and 11.1% (low- to middle-income countries)
• Average 12-month prevalence: 5.5% (high-income) and 5.9% (low- to middle-income)
• Female-to-male ratio ≈ 2:1 ^[2]

Why is depression more common in women? Several hypotheses ^[3]:

1. Women may be more willing to admit depressive symptoms
2. Depression in men may be misdiagnosed as alcohol-related disorder (men have higher rates of comorbid alcohol abuse)
3. Social disadvantages experienced by women
4. Female hormones (particularly oestrogen fluctuations) may sensitise the brain to the effects of stress — this explains perimenstrual, postpartum, and perimenopausal vulnerability windows

Hong Kong context:

• Lifetime prevalence of MDD in Hong Kong has been estimated at approximately 8-10% in community surveys
• Elderly depression is a particular concern given Hong Kong's ageing population
• Significant treatment gap exists — many patients present with somatic complaints rather than mood symptoms (especially in Chinese culture where psychological distress is often "somatised")

• Lifetime risk ~4%, higher in women and divorced individuals ^[3]
• Usual onset in early adulthood; may last throughout life → sometimes called a "depressive personality"

• Very commonly seen in primary care (6.9% prevalence) ^[3]
• Commonly present with prominent somatic symptoms to healthcare providers

• Lifetime prevalence: approximately 1-2% for Bipolar I; up to 4-5% for full bipolar spectrum
• No gender and ethnic difference ^[1]
• Risk factors include: high-income countries (may be due to referral bias), low income, separated/divorced/widowed status ^[1]
• Family history of bipolar disorder and schizophrenia: monozygotic concordance 40-70%, lifetime risk in first-degree relatives 5-10% (roughly 7 times higher than general population risk) ^[1]

Monoamines including serotonin, norepinephrine, and dopamine are relevant to mood regulation, and play an essential role in the regulation of other bodily functions. ^[4]

Low levels of serotonin metabolites have been found in the brains of suicide decedents and spinal fluids of depressed patients. ^[4]

Dopaminergic neurons in the mesolimbic reward pathway are diminished in the brains of suicidal decedents with depression. ^[4]

Mood symptoms emerged among patients who took propranolol (a beta-blocker that blocks noradrenergic signalling). ^[4]

Besides monoamines, abnormalities in glutamate, GABA, and substance P have been detected in patients with depression. ^[4]

Hormonal changes in depression include: dysregulation of hypothalamic-pituitary-adrenal (HPA) axis, lower estradiol (in women) and testosterone (in men), decreased triiodothyronine and thyroid-stimulating hormone, and diminished BDNF (brain-derived neurotrophic factor) level. ^[4]

Why does HPA axis dysregulation matter?

• Chronic stress → sustained cortisol elevation → direct toxic effect on hippocampal neurons (which are rich in glucocorticoid receptors) → hippocampal atrophy → further loss of HPA negative feedback → more cortisol → vicious cycle
• This explains why early life stress can structurally predispose to depression decades later

Cognitive distortions are prominent in depression and form the basis of Cognitive Behavioural Therapy (CBT). Key distortions include: ^[4]

Psychoanalytical theory: loss of an 'object', insecure attachments also contribute to understanding depressive vulnerability. ^[4]

Aaron Beck's "cognitive triad" of depression describes negative views of:

1. Self ("I am worthless")
2. World ("Everything is terrible")
3. Future ("Nothing will ever get better")

The current DSM-5-TR and ICD-11 classification uses a combination of aetiology, symptom pattern, and course ^[3]:

The old classification by presumed aetiology is now considered obsolete ^[3]:

• Endogenous (independent of external stress) vs. Reactive (response to external stress) — this distinction is no longer used because most depressive episodes have both endogenous and reactive elements

Current classification uses ^[3]:

This is a critical clinical issue ^[3]:

Consequences of misdiagnosis:

• Undertreated: increased suicidality, comorbid anxiety, substance abuse → ↓QoL, ↓functioning, ↑healthcare costs
• Overtreated: unnecessary side effects of mood stabilisers, increased sick role and disability claims
• Mistreated: antidepressants without mood stabiliser cover → less effective and risks manic switch and cycle acceleration ^[3]

Correct diagnosis requires history from the patient AND collateral history from informants, and structured screening tools (e.g., Mood Disorder Questionnaire [MDQ], Hypomania Checklist [HCL-32]). ^[3]

Correct diagnosis and treatment of bipolar disorder is often delayed by 5-7 years on average. ^[3]

The manic episode is essentially the "mirror image" of depression in many domains, though not a simple inversion:

1. Elevated, Expansive, or Irritable Mood

• The mood can be euphoric ("I feel on top of the world!") or irritable (especially when frustrated or thwarted)
• Pervasive — present most of the day, nearly every day
• Pathophysiology: dopaminergic hyperactivity in the mesolimbic pathway → excessive reward signalling

2. Increased Energy / Goal-Directed Activity

• Markedly increased energy levels, often with increased goal-directed activity (starting new projects, excessive planning)
• Or purposeless, non-goal-directed activity (psychomotor agitation)

3. Decreased Need for Sleep

• Characteristic: the patient feels rested after only 2-3 hours of sleep (contrast with insomnia in depression, where the patient wants to sleep but cannot, and feels unrested)
• Pathophysiology: overactivation of the reticular activating system and circadian disruption

4. Pressured Speech / Talkativeness

• Rapid, loud, difficult to interrupt
• Reflects racing thoughts being translated into speech

5. Flight of Ideas / Racing Thoughts

• Subjective experience of thoughts moving too fast; speech may jump from topic to topic with loose but identifiable associations
• Differs from "loosening of associations" in schizophrenia (where the connections are not identifiable)

6. Distractibility

• Attention easily drawn to unimportant or irrelevant external stimuli

7. Grandiosity / Inflated Self-Esteem

• Ranges from uncritical self-confidence to delusional grandiosity ("I am chosen by God," "I have special powers")
• Pathophysiology: excessive dopamine in reward circuits → overvaluation of self and abilities

8. Increased Risk-Taking / Pleasurable Activities with Potential for Painful Consequences

• Excessive spending sprees, sexual indiscretions, foolish business investments, reckless driving
• Reflects impaired judgment combined with increased reward-seeking behaviour

9. Psychotic Features (in Severe Mania)

• Mood-congruent delusions: grandiose delusions (believing one is a celebrity, deity, or has special powers), persecutory delusions (believing others are jealous/trying to stop them)
• Mood-congruent hallucinations: voices affirming special status

Hypomania is a less severe form of mania:

• Same symptom profile as mania BUT:
  • Shorter duration (≥ 4 days vs. ≥ 7 days for mania)
  • No psychotic features
  • No marked functional impairment or hospitalisation required
  • May be associated with increased functioning (the patient is more productive, sociable, creative)
• The challenge: patients often do NOT recognise hypomania as pathological — it feels good! Collateral history is essential.

• Episodes with both depressive and manic/hypomanic features simultaneously (e.g., grandiose thoughts but deeply dysphoric mood, or high energy but suicidal ideation)
• These carry a particularly high suicide risk because the patient has both the despair of depression and the energy/impulsivity of mania
• DSM-5 uses "with mixed features" specifier

Since bipolar depression accounts for the majority of illness duration in bipolar disorder, distinguishing it from unipolar depression is crucial. Clinical clues suggesting bipolar depression include:

~25% of bipolar disorder first presents as a juvenile depressive episode in their first episode ^[3]

Basic investigations: CBP, renal/liver function tests, thyroid function test. ^[4]

Others to consider if indicated by history and physical examination: blood alcohol level, blood and urine toxicology screen, HIV test, cosyntropin (ACTH) stimulation test (for Addison disease), EEG (for epilepsy), or CT/MRI (for organic brain syndrome or hypopituitarism). ^[4]

The provided notes reference a structured suicide risk assessment tool with scoring components ^[3]:

• Section B: Suicidal behaviour (suicidal ideation, plan, means, attempt, final acts/notes)
• Section C: Associated symptoms:
  • Depression (sleep disorder, anorexia/weight loss, withdrawal/loss of interest, hopelessness/helplessness, psychomotor retardation, depressed mood)
  • Hallucinations (derogatory, criticising, about death)
  • Delusions (guilt, death, persecutory)
  • Unstable mood (anxiety, panic, fear)
• Supervision levels: Normal (0-9), SO1 (10-18), SO2 (19-28), SO3 (29-41)

• Much less common in childhood ( < 1%, M:F ≈ 1:1) but increases drastically after puberty (1-year prevalence 4%, F > M ≈ 2:1)
• Aetiology: 5-HTTLPR variant associated with early-onset depression; cortisol-induced hippocampal atrophy; negative cognitive style, perfectionism; adverse life events
• Clinical features differ from adults:
  • Adolescence: similar to adults
  • Childhood: difficulty expressing sadness; more somatic complaints (abdominal pain, headache, anorexia, enuresis), irritable mood and anxiety, behavioural problems
  • Common comorbidities: 70% have anxiety disorder, conduct disorder, substance abuse, dysthymia
• Prognosis: episodic relapsing course; majority recover within 3 months but 15% last > 18 months
• ~25% of bipolar disorder first presents as juvenile depression

• Often under-recognised and undertreated
• May present with prominent cognitive symptoms (pseudodementia) — must differentiate from true dementia
• Higher rates of somatic presentation
• Associated with medical comorbidities, functional decline, bereavement, social isolation, and polypharmacy
• Higher suicide completion rates compared to younger adults (elderly men have the highest completed suicide rate of any demographic)

Key DSM-5 change: Removal of the "bereavement exclusion" — depressive symptoms may be understandable/considered appropriate to significant loss (e.g., bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability). Exercise of clinical judgment based on the individual's history and cultural norms. ^[6]

This is the category you must never miss. The mechanism is either:

• Direct physiological effect on the brain (e.g., hypothyroidism → reduced monoamine synthesis; Cushing's → cortisol-mediated hippocampal damage)
• Non-specific stressor (e.g., chronic pain, cancer diagnosis → psychological burden leads to depression)

Depression can be associated with medical conditions: ^[6]

Investigations to rule out secondary causes ^[3][4]:

The bipolar spectrum: BP I has severe mood episodes; BP II has milder manic symptoms with a prominent depressive element and can have the same degree of long-term impairment as BP I; BP spectrum patients are bothered by frequent mood changes and can be mistaken as borderline personality disorder. ^[7]

This is the bread-and-butter diagnosis. Learn it cold.

At least 2 weeks' duration. ^[6]

Clear-cut changes in affect, cognition, and neurovegetative functions. ^[6]

5 or more of the following symptoms are present; at least 1 of the symptoms is either (1) or (2): ^[6]

Additional DSM-5 criteria: ^[6]

• Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
• The episode is not attributable to the physiological effects of a substance or to another medical condition
• Not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders
• Absence of previous manic or a hypomanic episode (if present → bipolar disorder, not MDD)

DSM-5 Specifiers for MDD

Specifiers for major depressive disorder: ^[6]

Key changes from DSM-IV: ^[6]

• Removal of the "bereavement exclusion" — depressive symptoms may be considered appropriate to significant loss, but clinical judgment is exercised
• Dysthymia → persistent depressive disorder (now includes both chronic MDD and previous dysthymic disorder)
• Introduction of disruptive mood dysregulation disorder and premenstrual dysphoric disorder

DSM-5 criteria for manic episode: ^[7]

A distinct period of elevated, expansive or irritable mood and increased goal-directed activity lasting at least 1 week. ^[7]

Three or more (4 if mood is only irritable) of the following: ^[7]

Additional criteria: ^[7]

• Marked impairment in functioning, observable by others, to necessitate hospitalization, or there are psychotic symptoms
• Not due to alcohol, substance, or medical conditions

DSM-5 criteria for hypomanic episode: ^[7]

• At least 4 days of elevated, expansive, or irritable mood and increased activity or energy
• 3 or more of manic symptoms (same DIG FAST list)
• Change in functioning observable by others but not severe enough to cause marked impairment, to necessitate hospitalization, and there are no psychotic symptoms

The key differences from mania:

Often missed by patients and doctors resulted in delayed diagnosis. ^[7] Why? Because hypomania often feels good — the patient is more productive, sociable, and creative. They don't present complaining about feeling great. This is why collateral history from family/friends is essential.

DSM-5 criteria for bipolar I disorder: ^[7]

• Most cases have both manic and depressive episodes
• There is a predominant polarity; more manic or more depressive episodes
• Presence of one single manic episode already satisfies criteria for bipolar I disorder (this occurs in only 5%) ^[7]

This is a critical conceptual point: you do NOT need a depressive episode to diagnose Bipolar I. A single manic episode is sufficient. The logic: mania is such a specific and dramatic clinical phenomenon that its occurrence essentially defines the disorder.

DSM-5 criteria of bipolar II disorder: ^[7]

• At least one hypomanic episode
• At least one previous depressive episode
• Never has a manic or mixed episode
• Depressive episodes are more common in bipolar II disorder ^[7]

If a patient with Bipolar II ever has a full manic episode, the diagnosis is reclassified to Bipolar I.

These should be ordered for every patient presenting with a mood disturbance:

Basic investigations: CBP, R/LFT, thyroid function test. ^[4]

Others: blood alcohol level, blood and urine toxicology screen, HIV test, cosyntropin (ACTH) stimulation test (for Addison disease), EEG (for epilepsy) or CT or MRI (for organic brain syndrome or hypopituitarism) should be considered if indicated by history taking and physical examination. ^[4]

These are crucial for quantifying severity, tracking treatment response, and research — but they are explicitly useful in clinical practice and research but not diagnostic. Should not be used as a substitute for a clinical diagnosis made from a thorough interview. ^[6]

For bipolar disorder screening:

• Mood Disorder Questionnaire (MDQ) — screens for lifetime history of manic/hypomanic symptoms ^[5]
• Hypomania Checklist (HCL-32) — more sensitive for detecting hypomania ^[5]

The comprehensive assessment follows this structure ^[3]:

1. History Taking — structured approach to elicit:

2. Physical Examination — including general, neurological, and endocrine systems ^[3]

3. Investigations — as detailed above

When a mood episode includes psychotic features, distinguishing between mood-congruent and mood-incongruent psychosis is diagnostically important:

In mania, psychotic symptoms indicate the diagnosis of mania with psychotic features: delusions are often mood-congruent (grandiose, persecutory linked to status); 10-20% may have first-rank symptoms but these are usually fleeting ^[5].

The approach follows a stepped-care model (NICE guidelines) ^[3]:

Treatment of manic episode: ^[7]

Step 1: Monotherapy ^[7]

Step 2: Combination — Lithium/Valproate plus atypical antipsychotics ^[7]

Step 3: Reevaluate diagnosis and consider ECT (need of rapid response, e.g., high violence risk) ^[7]

Hospitalisation is necessary in all but the mildest cases of mania (insight is often impaired early) ^[5]

Drug options for acute mania ^[5]:

Critical considerations ^[5]:

• ALWAYS avoid/stop use of antidepressants (trigger mania)
• Ensure drug compliance by therapeutic drug monitoring
• Pregnancy: prefer haloperidol (not associated with ↑risk of congenital anomalies) → risperidone, quetiapine, olanzapine
• Treatment duration: gradual ↓dose with clinical improvement; continue treatment for ≥ 6 months and ≥ 8 weeks after complete remission (↓rebound mania) ^[5]

Acute treatment of bipolar depressive episodes: Because of the recognised risk of switching to manic or mixed episodes and the high risk of suicide, referral to a specialist should be considered. ^[7]

Treatment of bipolar depressive episode: ^[7]

Step 1: Monotherapy — Lithium, Lamotrigine OR Quetiapine ^[7]

Step 2: Combination — Add Antidepressants (SSRI OR Venlafaxine) to monotherapy OR Combine two monotherapy agents ^[7]

Step 3: Reevaluate diagnosis and consider ECT (for patients with high suicidal risk) ^[7]

Treatment is NOT identical to unipolar depression ^[5]:

• Conventional antidepressants are (1) less effective in treating bipolar depression, (2) associated with risk of inducing mania, (3) associated with risk of inducing rapid cycling ^[5]
• Not all mood stabilisers are equally effective at treating mania and depression — lamotrigine, quetiapine, and lithium are more useful for bipolar depression ^[5]
• SSRIs may be effective but may induce mania; TCAs and SNRIs have even higher risk of inducing mania ^[5]
• Antidepressants, when used, should be combined with antipsychotic or mood stabiliser ^[5]

Avoid antidepressants if possible; if used, limit dose and duration. ^[7]

Indication for prophylactic treatment: ^[7]

• Established bipolar disorder — recurrent episodes of mania or depression
• Severe single episode with suicidal attempts, psychotic episodes and significant functional impairment (to prevent future relapse)
• Recurrence rate reduces by 50% for maintenance vs. discontinuation
• Gradual discontinuation better than abrupt discontinuation ^[7]

General guidelines for prophylaxis for bipolar I: ^[7]

Monotherapy: Lithium or Valproate or Quetiapine ^[7]

Psychosocial (augmentation): ^[7]

• Psycho-education
• Cognitive behavioural therapy
• Interpersonal and social rhythm therapy
• Family or carer-focused treatment
• Peer-support
• Intensive case management
• Less hostile, more supportive, better drug compliance ^[7]

How long is the prophylactic treatment? ^[7]

• No strict guidelines, probably lifelong
• At least a few years without relapse (cases that have no relapse for more than 10 years relapse after discontinuation of treatment)
• Absence of subsyndromal symptoms between mood episodes is a prerequisite ^[7]

Relative efficacy of maintenance agents ^[5]:

Atypical antipsychotics look promising as mood stabilisers, but limited by metabolic side effects. ^[7]

Lithium is still an important drug, given that it is the only mood stabiliser to reduce suicide. ^[7]

Atypical antipsychotics have a dual role: antimanic (dopamine blockade) and mood-stabilising properties.

Where prompt action is needed, e.g., strongly suicidal. ^[6]

Indications ^[3]:

• Emergency: life-threatening depression (e.g., actively suicidal, refusing food/fluids, depressive stupor)
• Refractory: failed adequate trials of antidepressants
• Catatonia: life-threatening, treatment-resistant
• Mania: pregnant, life-threatening, persistent and treatment-resistant
• Puerperal psychosis: with prominent mood symptoms (rapid treatment to allow reuniting with baby)
• Selective treatment-resistant schizophrenia
• Previous good response to ECT
• ECT is especially effective for those with psychosis and/or psychomotor retardation ^[3]

Administration ^[3]:

• Course: 6-12 treatments, 2-3 per week
• Process: short-acting induction agent + muscle relaxant (5 min GA) → psychiatrist applies two scalp electrodes → electric pulse induces generalised tonic-clonic seizure lasting at least 15 seconds
• Unilateral vs bilateral: bilateral more effective but may cause more cognitive impairment; if unilateral, contralateral to dominant hemisphere

Side effects: headache, confusion, memory impairment. ^[6] Also consider need for anaesthesia, costs and inconvenience to the patient, stigma. ^[6]

• Cognitive impairment: acute confusion, anterograde or retrograde amnesia → generally short-lived (lasting a few days after ECT) ^[3]
• General: headache, nausea, muscle pain

Mortality: 2-4 per 100,000 (comparable to other minor surgery under GA); usually related to cardiopulmonary events ^[3]

Contraindications: no absolute contraindication; relative contraindications include ^[3]:

• Heart disease (recent MI, heart failure, ischaemic heart disease)
• Raised intracranial pressure
• Risk of intracranial haemorrhage (HTN, recent stroke)
• Poor anaesthetic risk

Non-invasive; hand-held, plastic-coated coil placed close to the scalp. ^[6]

• Uses external magnetic field to stimulate generation of action potentials and firing of neurons ^[3]
• Suitable for medically unwell patients who cannot tolerate antidepressants or ECT ^[3]
• Side effects: minimal, but only available in selected centres ^[3]

• Non-invasive; constant, low-voltage DC via electrodes on the head ^[3]
• Anode and cathode ↑/↓ cortical activity respectively → modulates neuronal network activity ^[3]
• NOT suprathreshold (unlike TMS, ECT) → limited to adjunctive use only ^[3]
• Side effects: minimal, but only available in selected centres ^[3]

WHO: Over 700,000 people commit suicide every year and many more attempt suicide. One of the major causes of suicide is depression. ^[6]

Depression raises suicidal risk — increase in suicide risk attributable to depression was 20-fold. ^[6]

Suicide was the cause of death in 6% of patients with an affective disorder, and the risk would be even higher in those with psychiatric comorbidities. ^[6]

In a longitudinal study in Sweden spanning over half a century, the long-term suicide risk in subjects with depression was 6.0% after 54-64 years of follow-up. ^[6]

From the senior notes: > 20× risk of suicide in MDD; can approach 15% in those severe admitted cases ^[3].

Why does depression cause suicide? The pathophysiology is multi-layered:

• Hopelessness — the cognitive triad (negative view of self, world, future) creates a perception that suffering is permanent and inescapable
• Serotonergic deficiency in the prefrontal cortex → impaired impulse control → inability to resist suicidal urges
• Psychomotor retardation paradox — severely depressed patients may be too retarded to act on suicidal thoughts; the dangerous period is when energy returns (early treatment response) before mood improves, giving the patient the "energy to act"
• Psychotic features — command auditory hallucinations, delusions of guilt/nihilism can directly drive self-harm

Suicide risk in bipolar disorder is among the highest of any psychiatric condition:

• ~8% of hospitalised males and 5% of hospitalised females die by suicide over 40 years of follow-up ^[5]
• Risk is highest during depressive episodes and mixed states (combination of despair and impulsive energy)
• The distress caused by untreated mood symptoms results in increased suicidality, comorbid anxiety, and substance use disorders ^[7]

Lithium is still an important drug, given that it is the only mood stabiliser to reduce suicide. ^[7] Why? Lithium's anti-suicidal effect appears to be partially independent of its mood-stabilising properties — it may directly reduce impulsivity and aggression via serotonergic modulation.

This is why depression after myocardial infarction is a recognised independent risk factor for cardiac mortality — it's not just "feeling sad about being sick."

• Depression itself is associated with insulin resistance via cortisol and inflammatory pathways
• Many psychotropic medications worsen metabolic parameters:
  • Atypical antipsychotics (especially olanzapine, clozapine) → significant weight gain, dyslipidaemia, hyperglycaemia, new-onset type 2 diabetes
  • Mirtazapine → weight gain via H1 antagonism (stimulates appetite)
  • Lithium → weight gain, hypothyroidism (both contribute to metabolic syndrome)
  • Valproate → weight gain, polycystic ovary syndrome

For bipolar disorder specifically: ↑cardiovascular disease / metabolic syndrome (medication side effects, poor lifestyle) is a major contributor to the reduced life expectancy ^[5].

Atypical antipsychotics look promising as mood stabilisers, but limited by metabolic side effects. ^[7]

Substance abuse is both a complication of and contributor to mood disorders, creating a vicious cycle:

• Depression: alcoholism is the most common comorbidity (occurs in ~40% of alcoholics); depression may drive self-medication with alcohol, and chronic alcohol use depletes monoamines, worsening depression ^[3]
• Bipolar I: alcoholism in 60% of patients — during manic episodes, hyperexcitability and impulsivity lead to ↑alcohol intake; alcoholism aggravates bipolar disorder and is associated with ↑suicide rate ^[3]
• Consequences: liver disease, nutritional deficiency (Wernicke-Korsakoff), accidents, violence, social deterioration, non-adherence to psychiatric medications

• Depression is one of the leading causes of disability worldwide (WHO Global Burden of Disease)
• Cognitive symptoms (poor concentration, indecisiveness, psychomotor retardation) directly impair work performance
• Only ~25% of those with recurrent major depression achieve 5-year clinical stability with good social and occupational performance ^[3]
• Bipolar disorder: only < 20% achieve a 5-year period of clinical stability ^[5]

• Social withdrawal (driven by anhedonia and anergia) → isolation → further worsening of depression
• Mania: reckless decisions, extravagant spending, sexual indiscretions, aggressive behaviour → damaged relationships, financial ruin, legal problems
• Advanced statements are recommended for bipolar patients to address social implications of poor judgment during manic states ^[5]

• Caregiver burden is significant — mood disorders are chronic relapsing conditions
• High expressed emotion (criticism, hostility, over-involvement) in families predicts relapse
• Family psychoeducation is a critical intervention to reduce relapse rates ^[7]
• Children of depressed parents: ↑risk of developing depression themselves (genetic + environmental), attachment difficulties, behavioural problems

• Acute episodes: poor concentration, indecisiveness, psychomotor slowing — these are state-dependent and typically improve with remission
• Chronic/recurrent depression: cumulative hippocampal volume loss (cortisol-mediated neurotoxicity) can lead to persistent cognitive deficits even between episodes
• In elderly patients: depressive pseudodementia can be indistinguishable from early dementia; importantly, depression in late life is a risk factor for subsequent true dementia

Staging of illness: ^[7]

• Stage 1: High-risk group (positive family history) or patients with subsyndromal symptoms
• Stage 2: Patients with a few episodes and optimal functioning
• Stage 3: Recurrent episodes and decline in functioning and cognition

Neuroprogression theory: worse prognosis with frequent relapses. ^[7]

Increased risk of future development of dementia. ^[7]

This is a crucial concept — bipolar disorder is increasingly recognised as a neuroprogressive illness. With each mood episode, there is accumulative neuronal damage (via excitotoxicity during mania, cortisol toxicity during depression, and neuroinflammation). This manifests as:

• Global cognitive deficits (attention, memory, executive function) that may persist even in euthymic periods ^[5]
• Progressive functional decline
• Increased risk of developing dementia in later life

Why do frequent relapses worsen prognosis? The "kindling" model explains that early episodes require a stressor to trigger them, but successive episodes become increasingly autonomous and easier to trigger — the brain becomes sensitised. Each episode causes further neuroplastic damage, creating a self-perpetuating cycle. This is the strongest argument for aggressive maintenance treatment and relapse prevention.

• Recurrence: ~80% will recur; average ~4 further episodes in 25 years
• Usually associated with progressively shorter intervals between episodes
• ~50% do not have complete symptom remission between episodes (residual symptoms)
• ~10-20% develop a chronic unremitting course

Prognosticants for relapse ^[3]:

1. Incomplete symptomatic remission
2. Early age of onset
3. Poor social support
4. Poor physical health
5. Comorbid substance abuse
6. Comorbid personality disorder

• Onset ~20 years; usually begins as depression with first manic episode occurring ~5 years later
• Manic episodes usually self-limited, resolving within ~6 months even if untreated
• 2-year outcome after first mania: 98% syndromal recovery, 72% symptomatic recovery, 43% functional recovery, 40% relapse
• Further mood episodes occur in ≥ 90% of manic patients; usually ~4 major episodes per 10 years
• Depressive episodes far outnumber manic episodes in both Bipolar I and II
• Patients on maintenance treatment with no relapse for many years CAN still relapse after cessation — relatives should be educated on prodromal symptoms to allow early treatment ^[5]

Recurrence rate in first-episode bipolar disorder: naturalistic 1-year follow-up showed high rates of recurrent mood episodes, with depressive episodes predominating. ^[7]

Poor prognostic factors for bipolar disorder: ^[7]

• Early onset
• Greater severity, mixed episodes, repeated episodes, previous hospitalisations
• Residual symptoms, cognitive impairment
• Poor insight, side effects of medications
• Comorbid substance or personality disorder

Prognosis: poor — only < 20% of bipolar patients achieve a 5-year period of clinical stability ^[5].

Bipolar II disorder has a relatively better prognosis than Bipolar I as a positive prognostic factor ^[5].