Module 14: Introduction to Mood Disorders

Mood Disorders

• A form of affective disorders

• Includes:

  • Major depressive disorder (MDD)

  • Bipolar disorder (BPD)

  • Seasonal Affective Disorder → type of depression worse in winter

• They cost the economy $210 bn in 2010

• Higher distribution of these depressive disorders in the US (difference in diagnostics and healthcare system)

Major Depressive Disorder: Epidemology

• Affects ~5% of the global population (much more common than BPD at ~1%)

• Twice as common in women than men

• Can affect all ages, but peaks in the 30s–40s

• Age of onset is decreasing

Bipolar Disorder Epidemology

• Typical onset: Between 15–19 years old

• Rare after age 40

• Equally affects males and females

Economic Burden of Depression

• Costs largely come from lost productivity and workplace absence

• Direct medical costs also contribute significantly

• Suicide is a major factor — those with MDD have a much higher suicide rate than the general population

• Only 50% of medical costs are for depression treatment

• The other 50% is due to co-morbidities (e.g., heart disease, CVDs, diabetes, other psychiatric disorders)

  • People with depression have higher rates of co-morbid conditions

Diagnostic Criteria Used to Diagnose Depression

• 2 criteria present:

  • DSM-5: a diagnostic and Statistical Manual of mental disorders – issued by the America psychiatric Association and is used in the UK

  • ICD-11 – a product of WHO and is used by some countries as a diagnostic standard for depression

    • Subtle differences in diagnostic criteria, but tend to overlap

2 Categories of Mood Disorders

• Low mood e.g.

  • MDD

  • Dysthymia – long-lasting low-grade depression

• Elevated mood and low mood

  • Bipolar disorder – periods of symptoms similar to MDDs and periods where mood is abnormally elevated

MDD: Diagnostic Criteria

• Depressed mood: For children and adolescents, this can also be an irritable mood

• Diminished interest or loss of pleasure in almost all activities (anhedonia)

  • Must have at least one of these 2

• Significant weight change or appetite disturbance

• Sleep disturbance (insomnia or hypersomnia)

• Psychomotor agitation or retardation

• Fatigue or loss of energy

• Feelings of worthlessness

• Diminished ability to think or concentrate, indecisiveness

• Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide

• In a two-week period, must have 5 of the criteria (inc. at least one of the first two).

• Must cause distress or impairment and do not have another cause e.g. drug abuse.

• Range of different sets of diagnostic criteria – possible for 2 people with depression to have completely different symptoms

Diagnostic Specifiers

• Used in adjunct to the mainstream diagnosis make the diagnosis more precise

• Can be used to describe:

  • symptoms

  • severity

Diagnostic Specifiers: Based on Symptoms

• Anxious distress ** e.g. MDD with Anxious Distress

• Atypical features **

• Mixed features

• Melancholic features **

• Catatonia

• Post partum onset **

• Seasonal pattern **

• Psychotic features

  • mood congruent

  • mood incongruent

Diagnostic Specifiers: Based on Severity

• Mild

• Moderate

• Severe

• With psychosis

• In partial remission

• In full remission

• Single/recurrent (cause of remission) – single episode or recurrent condition

MDD with Specifier Symptoms: Melancholic Features

• Common form of depression

  • Insomnia

  • diurnal mood variations (worse in morning)

  • anorexia – loss of appetite

  • Psychomotor retardation or agitation

  • lack of joy - anhedonia

  • feelings of guilt

MDD with Specifier Symptoms: Atypical Features

• weight gain

• worse in evening

• increased sleep

• sensitivity to rejection

• anxiety

• feeling of heaviness, leaden paralysis

• maintained ability to experience joy – different to what is typically seen

NICE Diagnostic Criteria for MDD

• Use DSM 5.

• They stratify depression as:

  • Less severe (PHQ-9 < 16)

  • More severe (PHQ-9 ³ 16)

• Based on scores from the Patient Health Questionnaire 9 –

  • Assess how badly someone is affected by each of the criteria in the DSM-9 – max score of 27

• The score obtained determines the treatment pathway recommended

Name Some The Features You Would Expect from MDD With Atypical Features and Anxious Distress: (Case Study → Male 58yrs)

• Episodes over a period of >10 years

• Symptoms - Low mood, irritability

• Lack of ability to concentrate

• Loss of interest in many activities, able to perform day-to-day tasks but even minor obstacles can be overwhelming

• Fatigue

  • All relate to MDDs

• Still able to react to joyful events – not seen with melancholic depression

• Increased need for sleep

• Feeling of heaviness

• Increased appetite, weight gain

  • Symptoms give rise to ‘with atypical features’

• Anxiety: particularly catastrophising, health anxieties.

• Symptoms give rise to ‘with anxious distress’

Stats and Conclusions about Depression and BPD

• Prevalence and age distribution depend on how and where it's measured

• 2–7% of people experience depression at any given time

• Depression can affect all ages, tends to have an early onset, and is more often diagnosed in women

• Bipolar disorder has a lower prevalence and shows no sex difference

Bipolar Disorder (BPD)

• Aka manic depression

• Consists of depressive episodes + manic episodes

• Diagnostic criteria for depressive episodes as per MDD

• Can be very disabling and suicide risk high (about 35% of people with BP attempt suicide)

BPD: Manic Episoderes

• Abnormally elevated, expansive or irritable mood and persistently increased activity or energy, present most of the time for at least a week.

  • Plus, three of the following (four if irritable mood):

  • inflated self-esteem, grandiosity

  • decreased need for sleep

  • more talkative than usual

  • flights of ideas, racing thoughts

  • distractibility

  • increase in goal-directed activity or psychomotor agitation

  • excessive involvement in damaging activities: hypersexuality, gambling, spending, foolish business ventures

• Episode causes marked impairment to function or has psychotic features e.g. delusions or hallucinations

• Subtypes of maina can help to define the subtypes of the disorder

BPD: Hypomania

• A subtype of mania categorised as:

  • mildly elevated mood and energy level

  • must produce a definite change in functioning that is noticeable to others

  • impairment not so great: individuals can be highly productive whilst hypomanic

  • often seen as a “personality trait” and so is often underdiagnosed

BPD: Mixed Episodes

• A subtype of mania categorised as:

  • A patient has elevated energy levels, psychosis etc. but is simultaneously depressed with a low mood

  • even higher risk of suicide

3 Subtypes of BPD

• BP1 – classic manic depression with full mania and involves periods of MDD

• BP2 – involves MDD episodes and hypomania

  • This may classified further as rapid cycling → more than 4 episodes in one year

• Cyclothymia – mild depression and hypomania that lasts for 2 years

Brain Areas Affected in MDD

• The prefrontal cortex, anterior cingulate cortex, hippocampus and amygdala atrophy

• Unsure how changes in these regions cause changes in thinking → likely that the brain circuits involved in regulating emotion are disrupted

Hippocampal Atrophy In Depression:

• Studies measured hippocampal volume in people with untreated depression.

• Found a negative correlation: the longer an individual is left untreated, the smaller the hippocampus becomes.

• After 10 years of untreated depression, the hippocampus can shrink by up to 30%

Prefrontal Cortex In Depression

• Area important in regulating emotion and exerting inhibitory control over the hypothalamus

• It undergoes structural changes, resulting in a lower glucose metabolism compared to the rest of the brain

• This may be due to a reduction in cell numbers rather than a decrease in individual cell metabolism

• Reduce activity in this area is likely a consequence of reduced cortical volume

• Activity of this area decrease, allowing for increase hypothalamic activity → acts to regulate cortisol levels, and may be cause of depression

Single Photon Emission Computed Tomography (SPECT) Study

• Examined brain metabolism during depressive and manic phases in BPD.

• Manic phase: Brain metabolism increases in certain regions.

• Depressive phase: Metabolism is reduced, particularly in the prefrontal cortex (PFC).

• PFC activity is decreased during depression and increased during mania — but these changes are not diagnostic.

• Other brain areas are also implicated in mood disorders.

• Overall, PFC abnormality alone is not sufficient for diagnosis.

Damage to Ventral Pre-Frontal Cortex

• In women who attempted suicide via gunshot wound to the head, depression symptoms abated after the injury.

• Brain scans showed significant damage to the ventral PFC.

• A suicide attempt via crossbow caused left PFC damage.

  • The individual survived and was described as docile, resigned, and emotionally indifferent — a change in personality.

    • This has been called "Phineas Gage in reverse."

• This suggests the ventral PFC plays a key role in regulating emotion, and its dysfunction may contribute to depression.

Amygdala

• an almond-shaped structure involved in emotional regulation, e.g. processing emotions, rewards, threats, and social significance.

• In depression, the amygdala shows:

  • Overactivity when exposed to sad stimuli, and underactivity when exposed to positive stimuli (differential processing of emotions).

• Involved in organising endocrine, autonomic, and behavioural responses to stressors or threats.

  • Abnormalities in these functions resemble recessive amygdala activity in depression, leading to excess hormone and autonomic nervous system activity.

• Meta-analysis suggests a reduced volume in MDD

• It's response to positive vs. negative stimuli appears perturbed in depression.

2 Mechanisms of Depression

• Monoamine hypothesis: dysfunction of serotonergic and noradrenergic transmission – root cause of depression

• Chronic stress → dysfunction of the HPA axis, prefrontal cortex and hippocampus

Iproniazid (1952)

• Initially developed to treat TB → had anti-depressive properties

  • Patients seemed “inappropriately happy

  • Approved as Anti-Depressant in 1958

  • Irreversible MAO inhibitor – blocks metabolic enzyme

Reserpine

• An early anti-hypertenisve and antipsychotic

• Blocks VMAT (Vesicular Monoamine Transporter), depleting monoamine levels.

  • It was suggested that it could induce depression by depleting monoamines.

Connection Between Monoamines and Depression

• Serotonin levels are often lowered in patients with depression.

• Tryptophan, a serotonin precursor, depletion can lower mood and induce relapse in depression.

• This led to the development of the "monoamine hypothesis of depression," which suggests that decreased levels of monoamines (like serotonin, dopamine, and norepinephrine) are linked to the development of depression

Evidence for the Monoamine Hypothesis

• Most antidepressant (AD) drugs work by altering serotonergic or noradrenergic transmission – strong support for the hypothesis.

  • These drugs affect transmission very quickly (within hours to minutes).

Problems With The Monoamine Hypothesis

• Antidepressant effects are delayed by 2-4 weeks, despite the fast action on neurotransmission.

• The hypothesis suggests that this delay is due to changes in receptor expression or desensitisation over time.

Hypothalamic Pituitary Adrenal Axis (HPA)

• Involves the hypothalamus, anterior pituitary gland, and adrenal cortex in a hormone cascade that results in cortisol production.

• The hypothalamus produces CRF/CRH, which stimulates the APG to release ACTH, acting on the adrenal cortex to produce cortisol, which is then released into the bloodstream.

• Cortisol is a powerful physiological regulator, affects the immune system and metabolism.

• Negative feedback regulation: Cortisol acts on GC receptors in the APG and hypothalamus, decreasing the production of CRF/CRH and ACTH to reduce cortisol levels.

• Stress causes an increase in plasma cortisol levels, helping to mobilize glucose, which is essential during stressful situations.

HPA Axis in Depression

• 50% of depressed patients have hyperactivity of the axis

• 80% of severely depressed patients have HPA axis hyperactivity

  • Reflected in increased cortisol levels

• (Mechanism may be particularly important in certain types of depression)

Dexamethasone Suppression Test

• Potent synthetic glucocorticoid acts at the GC receptors in the APG and hypothalamus to decrease CRH, ACTH and cortisol → used to test the negative feedback loops in the HPA axis

• It reduces cortisol by 85% in controls, and 45% in depressed

  • In depressed patients – negative feedback loops don’t work properly – may be caused by chronic stress

Chronic Stress and HPA Axis

• Results in elevated levels of hydrocortisone, cortisol over, compromising the negative feedback loops (Receptors may become less sensitive to cortisol) → acts to significantly increase cortisol levels

• High levels of CRF/CRH are also seen – seen as important molecules in depression

Effect of Cortisol/CRF on the Brain

• Dysfunctional HPA axis leads to increased cortisol and increased CRF levels.

• The hippocampus, PFC (prefrontal cortex), and amygdala have receptors for cortisol and CRF.

• Cortisol and CRF have negative effects on these brain regions:

  • Promote apoptosis (cell death)

  • Decrease neurogenesis (formation of new neurons)

  • This may underlie structural changes in these areas, which can contribute to the development of depression.

• In Cushing's syndrome, where cortisol levels are elevated due to a tumour or long-term glucocorticoid treatment, depression is frequently observed.

Depression and HPA Axis

• Problems withthe HPA axis frequently een

• The hypothalamus is regulated by the PFC, hippocampus and amygdala – in depression, these brain regions are dysfunctional = resulting in a loss of regulation

• A depressed individual has a loss of negative feedback loops and loss of regulatory input into the hypothalamus

Origin of HPA Axis Problem

• Some individuals experience long periods of sustained stress but do not develop depression.

• Vulnerabilities to depression may be influenced by a combination of genetic and epigenetic factors.

  • Genetic factors: Polymorphisms in genes involved in the HPA axis.

• Early childhood trauma/deprivation can lead to HPA axis hyperactivity that persists into adulthood, even if depression is not currently present.

  • This may be due to epigenetic modifications, which explain why early childhood problems are risk factors for depression in later life.

• Epigenetic changes in HPA axis genes may act as predictors of depression in adulthood

Actions of Anti-Depressants

• Most act through monoamine transmission, which can alter neurogenesis and apoptosis, helping to restore the structure of critical brain regions.

• This process takes time, which can explain the delay in the clinical effects seen

• If brain regions return to normal function, it may restore HPA axis function, reducing CORT and CRF.

  • This reduction can promote neurogenesis and decrease apoptosis, creating a virtuous cycle of improvement.

Use of Twin Studies in Mood Disorders

• Recognised that disorders are heterogenous and the identification of genetic factors may allow for tailored treatments to an individual’s specific conditions

• Identify genetic factors for mood disorders by yielding a concordance rate—the percentage chance that one twin will develop a disorder if the other already has it.

• A 100% concordance rate suggests strong genetic involvement.

• A concordance rate less than 100% but greater than the general population's disease prevalence suggests genetic factors at play.

  • Limitations: Twins share similar environments, so results can be confounded by environmental factors.

• Childhood trauma can cause epigenetic changes, increasing the risk of developing mood disorders.

• Environmental factors (e.g., abusive or alcoholic parents) may influence both twins similarly, adding complexity to the results.

GWAS Studies

• use of a larger population

• Presence of confounding factors that make data interpretation difficulty

• Results indicate ~40% of the risk of MDD is genetic

  • Recognised that disorders are heterogenous and the identification of genetic factors may allow for tailored treatments to an individual’s specific conditions

MDD and Genetics

• No single depression gene, but rather a large number of genetic difference that each contribute to the risk fo developing MDD

Genes Linked to MonoAmine Transmision

• Studies have found polymorphisms in the SERT transporter increase risk of depression by 20%

  • Inconsistencies in findings assessing polymorphism in serotonin receptors and metabolic enymes like MOA

• Strong association between depression and polymorphisms in the DAT and D4 dopamine receptor

Setraline

• Primarily works by increasing serotonin levels in the brain by inhibiting its reuptake into neuron

• May inhibit dopaminergic mechanisms at high doses

• Caution with use as other DAT active drugs that were developed as anti-depressants have been withdrawn from the market due to side effects

Genes Linked to HPA Dysfunction

• Several polymorphisms have been linked to depression

• This includes genes for:

  • mineralocorticoid receptor,

  • corticotrophin releasing hormone receptor, 

  • FKBP5, a protein that modulates the sensitivity of the glucocorticoid receptor.

• Strong evidence for the role of epigenetic changes to HPA axis genes.

Other Genes Implicated in MDD

• Strong associations between polymorphisms in the G-protein subunit beta-3 and MDD, but the mechanism is unclear

• Methylenetetrahydrofolate reductase mutations have been linked to depression and a wide range of other psychiatric problems.

• The exact mechanism is unclear, → may impact the ability to metabolise folate and might compound environmental factors such as childhood neglect.

Genetics and BPD

• Very trong evidence that the disorder is heritable

• Estimated that the the genetic contribution to disease risk have been as high as 80% in twin studies.

  • No "bipolar gene", but a large number of risk factors that each produce only a small increase in the likelihood of developing this disorder.

• Genes implicated in disorder (identified through GWAS):

  • ANK3

  • CACNA1C

  • TRANK1

ANK3

• Gene implicated in BPD

• Codes for ankyrin B, a protein involved in neuronal myelination

CACNA1C

• Gene implicated in BPD

• codes for a voltage sensitive calcium channel that is known to be expressed in the brain → roles in both development and signalling

TRANK1

• Gene implicated in BPD → role is poorly understood

• The expression of its product is increased by mood stabilisers e.g. sodium valproate

• It is also associated with SZ

Potential Adaptativeness of Depression

• It is common and often debilitating.

• Some researchers suggest that it may have beneficial effects in certain conditions, which is why it has not been eliminated by evolution.

Evolutionary Hypothesis Behind Depression and Behavioural Shutdown

• Learned helplessness suggests depression might be an adaptive response, conserving energy when stressors are impossible to overcome.

  • Shown in animal models of depression

• In ancestral societies, withdrawing from activities during low food supplies could help conserve energy, increasing survival.

• This may extend to sickness behaviour, where individuals withdraw to avoid danger when ill, offering protection during vulnerable times.

  • may explain the high levels of anxiety seen with depression

Anxiety in Evolutionary Hypothesis of Depression

• May represent a state of hypervigilance, an evolutionary advantage when sheltering from danger, sickness or threats during illness.

• The hypervigilant state would have helped early humans stay alert and protect themselves while physically weak or sick → may explain the high levels of anxiety seen with depression

• Seen in aminal models: place young rats in a cage with a dominant adult male rat

  • best way to survive, is to be subservient and accept their position.

  • this ancient behaviour still permeates parts of modern society

Psychic Pain and Depression

• Physical pain that serves a purpose, telling us to stop doing something that is proving damaging to us.

• Possible that depression may serve a similar purpose i.e. it will make us withdraw from activities that are proving stressful.

Depression and Problem Solving

• Ruminations in depression may help individuals solve certain kinds of problems

• The condition may cause a behavioural shutdown, focusing energy on solving problems while reducing other distractions, which could have been helpful in survival situations.

  • may be important in solving social dilemmas e.g. whether to stay in a relationship

Measuring Depression

• Variety of questionnaire-based scales help doctors assess the severity of a patient’s depression.

• In the UK, the Patient Health Questionnaire 9 (PHQ-9) is commonly used, based on the DSM-5 symptom list, breaking down how frequently each symptom is experienced.

• The Hamilton Depression Rating Scale (HDRS or HAM-D) is another widely used tool recommended by NICE for assessing depression severity.