2.1.1 Unipolar Depression

Unipolar Depression

Prevalence and Incidence: According to the World Health Organization (WHO), depression is a leading cause of disability worldwide, with an estimated 264 million people affected globally. The lifetime prevalence of major depressive disorder (MDD) is approximately 15%, with women being twice as likely as men to experience MDD. The incidence of depression varies by age, with the highest incidence occurring in those aged 18-29 years.

Aetiology:

The aetiology of unipolar depression is complex and involves a combination of genetic, environmental, and psychosocial factors. Biological factors that contribute to depression include imbalances in neurotransmitters such as serotonin and noradrenaline, abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis, and genetic predisposition. Environmental factors such as chronic stress, trauma, and adverse childhood experiences can also increase the risk of developing depression.

Risk Factors for Depression	Description
Genetic	Heritability estimates range from 17% to 75%, families also have high rates of anxiety disorders and neuroticism.
Childhood experiences	Loss of a parent, lack of parental care, parental alcoholism/antisocial traits, childhood sexual abuse. Cumulative childhood disadvantage confers a greater risk.
Personality traits	Anxiety, impulsivity, obsessionality.
Social circumstances	Marital status (low rates for men associated with marriage, high rates with separation or divorce), lack of paid employment, lack of a confiding relationship.
Adverse life events	Particularly ‘loss’ events in vulnerable individuals.
Physical illness	Especially if chronic, severe, or painful. Neurological disorders have a higher risk. Higher rates were also noted in post-MI, diabetic, and cancer patients.

Presentation:

The clinical presentation of depression includes persistent feelings of sadness, hopelessness, and worthlessness, loss of interest in activities once enjoyed, changes in appetite and sleep patterns, fatigue, and difficulty concentrating. In severe cases, suicidal ideation may be present.

Core Symptoms	Description
Depressed mood	Persistent and unresponsive to changes in circumstances, with a possible diurnal variation.
Anhedonia	Lack of interest or pleasure in most activities.
Weight change	Significant loss or gain of body weight.
Disturbed sleep	Insomnia or hypersomnia, with early morning wakening in some cases.
Psychomotor agitation or retardation	Visible changes in movement.
Fatigue or loss of energy	Decreased levels of energy or feelings of fatigue.
Reduced libido	Decreased interest in sexual activity.
Feelings of worthlessness or excessive guilt	Persistent feelings of worthlessness or guilt that may be delusional.
Diminished ability to think or concentrate	Decreased ability to focus, think or make decisions.
Recurrent thoughts of death or suicide	Persistent thoughts of death or suicide, with or without attempts.

Psychotic Symptoms/Features	Description
Delusions	False beliefs, such as personal inadequacy, guilt, and responsibility for world events.
Hallucinations	False sensory perceptions, such as hearing accusatory voices or seeing tormentors.
Other Mood-Incongruent Psychotic Symptoms	Other false beliefs, such as persecutory delusions and delusions of control.

Other Features	Description
Significant anxious distress	Experiencing significant levels of anxiety.
Catatonic symptoms	A marked decrease in movement and responsiveness to the environment.
Depressive stupor	Extreme psychomotor retardation, where the individual is almost immobile.

Treatment:

The most effective treatment options for depression include psychotherapy and antidepressant medication. Cognitive-behavioural therapy (CBT) is a common form of psychotherapy that helps individuals identify and change negative thought patterns and behaviours. Antidepressant medication, such as selective serotonin reuptake inhibitors (SSRIs), work to increase the levels of serotonin in the brain and can alleviate symptoms of depression.

The National Institute for Health and Care Excellence (NICE) guidelines for unipolar depression provide recommendations for the assessment and treatment of this condition in adults. The following are some of the key recommendations:

1. Initial assessment: Healthcare professionals should conduct a thorough initial assessment of the person’s symptoms, including the severity of depression, any comorbid conditions, and the person’s preferences for treatment.
2. Non-pharmacological interventions: For mild to moderate depression, healthcare professionals should offer individual or group-based psychological interventions, such as cognitive-behavioural therapy (CBT) or interpersonal therapy (IPT), before considering medication.
3. Antidepressant medication: For moderate to severe depression or when psychological interventions have not been effective, healthcare professionals should consider offering antidepressant medication, such as selective serotonin reuptake inhibitors (SSRIs), in combination with psychological interventions.
4. Continuation and maintenance treatment: For people who have responded to treatment, healthcare professionals should offer continuation treatment for at least 6 months to prevent relapse. For those who have had multiple episodes of depression or a chronic course, maintenance treatment for at least 2 years is recommended.
5. Electroconvulsive therapy (ECT): For severe or life-threatening depression or for those who have not responded to other treatments, ECT should be considered.
6. Stepped care: Healthcare professionals should consider a stepped-care approach, where treatment intensity is increased if symptoms do not improve with initial interventions.

It is important to note that these guidelines are not prescriptive and that treatment should be tailored to the individual’s needs and preferences. Regular monitoring and review of treatment are also essential.

Antidepressants appear to exert antidepressant action by increasing the availability of monoamines (5-HT, NA, and DA) via one or more of the following mechanisms:

• Presynaptic inhibition of the reuptake of 5-HT, NA, or DA.
• Antagonist activity at presynaptic inhibitory 5-HT or NA receptor sites enhances neurotransmitter release.
• Inhibition of monoamine oxidase, reducing neurotransmitter breakdown.
• Increasing the availability of neurotransmitter precursors.

Although this net increase happens almost immediately following administration, the initial resolution of depressive symptoms generally takes 10–20 days. This suggests that the therapeutic effect involves mechanisms possibly related to receptor regulation over time or changes in intracellular signalling.

Common combinations:

• SSRI + trazodone or mirtazapine for those troubled by insomnia but who have responded well to the antidepressant effects of the SSRI.
• Venlafaxine + mirtazapine (as in the STAR*D study; for treatment resistance).
• Bupropion or mirtazapine + SSRIs or SNRIs to combat sexual dysfunction, which can be a consequence of SSRI or SNRI treatment.

Outcome:

With proper treatment, the majority of individuals with depression can recover and lead healthy and fulfilling lives. However, approximately 30% of individuals with depression may experience treatment-resistant depression, which is defined as the failure to respond to two or more adequate courses of antidepressant treatment.

	Unipolar Depression
Prevalence	15% lifetime prevalence
Onset	Varies by age, highest in those aged 18-29 years
Gender	Women twice as likely as men
Aetiology	Genetic, environmental, and psychosocial factors
Presentation	Persistent feelings of sadness, hopelessness, and worthlessness, loss of interest in activities once enjoyed, changes in appetite and sleep patterns, fatigue, difficulty concentrating, and suicidal ideation in severe cases
Treatment	Psychotherapy (CBT) and antidepressant medication (SSRIs)
Outcome	The majority can recover and lead healthy lives, but 30% may experience treatment-resistant depression

Important Studies

STAR*D study:

The Sequenced Treatment Alternatives to Relieve Depression (STARD) study is a landmark clinical trial that was conducted to evaluate the effectiveness of various treatments for depression. The study, which was conducted in the United States between 2001 and 2006, involved over 4,000 participants with major depressive disorder. The participants were randomized to receive various treatments, including medication and psychotherapy, and were followed for up to 12 months. The study provided valuable insights into the effectiveness of various treatments for depression and identified factors that can affect treatment outcomes, such as the severity of depression and the presence of co-occurring mental health conditions. The findings of the STARD study have had a significant impact on the field of psychiatry and have helped to inform the development of treatment guidelines for depression.

Study Name	Sequenced Treatment Alternatives to Relieve Depression (STAR*D)
Objective	To evaluate the effectiveness of various treatments for depression
Study Period	2001-2006
Participants	Over 4,000 individuals with major depressive disorder
Treatments	Medication and psychotherapy
Follow-up Period	Up to 12 months
Key Findings	Identified factors that can affect treatment outcomes, such as the severity of depression and the presence of co-occurring mental health conditions
Impact	Significantly influenced the field of psychiatry and informed the development of treatment guidelines for depression

Antidepressants:

Tricyclic antidepressants:

	Summary
Serotonin/NA (and DA) reuptake inhibition	Provides antidepressant effects.
Anticholinergic (antimuscarinic—M1)	Can cause dry mouth, blurred vision, constipation, urinary retention, drowsiness, confusion/memory problems (particularly in the elderly), and palpitations/tachycardia.
Adrenergic antagonism (α1)	Can cause drowsiness, postural hypotension (occasionally syncope), tachycardia, and sexual dysfunction.
5-HT2antagonism	Can provide anxiolytic effects, reduced sexual dysfunction, and sedation.
Antihistaminergic (H1)	Can cause drowsiness and weight gain.
Advantages	Well-established efficacy, large literature, possibly more effective in severe depression, and low cost.
Disadvantages	Toxicity in overdose may be less well tolerated than SSRIs, all TCAs may slow cardiac conduction and lower seizure threshold.
Contraindications	Acute MI, heart block, arrhythmias, IHD, severe liver disease, pregnancy, and lactation.
Cautions	Cardiovascular, liver, renal disease, endocrine disorders (hyperthyroidism, adrenal tumours, diabetes), urinary retention/prostatic hypertrophy, constipation, glaucoma, epilepsy, psychotic disorders, patients with thoughts of suicide, and elderly (use lower doses).
Significant interactions	Alcohol, anticoagulants, anticonvulsants, antihypertensives, antipsychotics, barbiturates, BDZs (rare), cimetidine, digoxin, MAOIs (rare), methylphenidate, morphine, SSRIs, smoking.
Monitoring	Good practice to monitor cardiac and liver function, U&Es, FBC, and weight during long-term therapy.

Usual maintenance dose and Max daily dose for Tricyclic Antidepressants (TCAs):

Drug	Usual maintenance dose	Max daily dose
Amitriptyline	100-150mg	150mg
Clomipramine	30-150mg	250mg
Dosulepin	75-150mg/day	225mg (hospital)
Doxepin	Up to 300mg/day	300mg
Imipramine	50-100mg/day	200mg
Lofepramine	70-210mg/day	210mg
Nortriptyline	75-100mg	150mg
Trimipramine	150-300mg/day	300mg

Monoamine oxidase inhibitors (MAOIs) and reversible monoamine oxidase inhibitors (RIMAs):

	Summary
Mode of action	MAOIs: irreversible inhibition of MAO-A and MAO-B, leading to accumulation of monoamines in the synaptic cleft. RIMAs: act by reversible inhibition of MAO-A.
Side effects	Risk of hypertensive crisis due to inhibition of intestinal monoamine oxidase, leading to the accumulation of pressor amines. Dietary tyramine and certain medications should be avoided. Other side effects include antimuscarinic actions, hepatotoxicity, insomnia, anxiety, appetite suppression, weight gain, postural hypotension, ankle oedema, sexual dysfunction, and possible dependency.
Indications	Usually used as second-line therapy for treatment-resistant depression/anxiety disorders.
Cautions	Caution is required in patients with cardiovascular disease, hepatic failure, poorly controlled hypertension, hyperthyroidism, porphyria, or phaeochromocytoma.
Advantages	Well-established efficacy in a broad range of affective and anxiety disorders.
Disadvantages	Dietary restrictions and drug interactions. RIMAs have fewer drug interactions than MAOIs.
Significant drug interactions	Antidiabetics, antiepileptics, antihypertensives, antipsychotics, barbiturates, BDZs, β-blockers, buspirone, cimetidine, dopaminergic, dextromethorphan, mazindol, pethidine, morphine, and 5-HT1 agonists. Always check data sheets.

Usual maintenance dose and Max daily dose for Monoamine oxidase inhibitors:

Drug	Usual maintenance dose	Max daily dose
Isocarboxazid	10–40mg/day	60mg/day
Moclobemide	150–600mg/day	600mg/day
Phenelzine	15mg every other day to 15mg qds	60mg/day (hospital 90mg/day)
Tranylcypromine	10mg/day	30mg/day (or greater if supervised)

Selective serotonin reuptake inhibitors:

	Summary
Serotonin reuptake inhibition	This leads to 5-HT in the synaptic cleft.
5-HT1Aagonism	Antidepressant, anxiolytic, anti-obsessive, anti-bulimic effects.
5-HT2agonism	Agitation, akathisia, anxiety/panic, insomnia, sexual dysfunction.
5-HT3agonism	Nausea, GI upset, diarrhoea, headache.
Advantages	Ease of dosing may be better tolerated than TCAs, less cardiotoxic, fewer anticholinergic side effects, and low toxicity in OD.
Disadvantages	Commonly cause nausea and GI upset, headache, restlessness, and insomnia, may be less effective for severe depressive episodes, and problems on discontinuation.
Contraindications	Manic episode, concomitant use of MAOIs.
Cautions	Variable and significant inhibitory effects on hepatic P450 (particularly CYP2D6) enzymes. Hence, take care when co-prescribing with drugs that undergo extensive liver metabolism and have a narrow therapeutic range.
Significant interactions	Variable for different agents—always check data sheets. Includes alcohol, anticoagulants, anticonvulsants, antipsychotics, BDZs, β-blockers, bupropion, buspirone, cimetidine, cyproheptadine, hypoglycemics, lithium, methadone, MAOIs, morphine, smoking, TCAs, theophylline, and warfarin.

Usual maintenance dose and Max daily dose for Selective serotonin reuptake inhibitors:

Drug	Usual Maintenance Dose	Max Daily Dose
Citalopram	20-60mg od	60mg
Escitalopram	5-20mg od	20mg
Fluoxetine	20-60mg od	60mg
Fluvoxamine	100-300mg	300mg
Paroxetine	20-50mg od	50mg
Sertraline	50-200mg od	200mg

References:

1. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). https://doi.org/10.1176/appi.books.9780890425596
2. Kessler, R. C., Berglund, P., Demler, O., Jin, R., Merikangas, K. R., & Walters, E. E. (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62(6), 593–602. https://doi.org/10.1001/archpsyc.62.6.593
3. Semple, D., Smyth, R., & Burns, J. (Eds.). (2013). Oxford handbook of psychiatry (3rd ed.). Oxford University Press.