Affective Disorders: Types, Causes, Symptoms and Treatments

Introduction

Affective disorders are a group of disorders with the essential feature of disturbance of mood, accompanied by a full or partial manic or depressive syndrome which is not due to any other physical or mental disorder.

Central features

• Alteration in mood
• Depression (most common)
• Low mood (less common): High or elated

Classification

1. Depression

2. Mania

3. Bipolar & Unipolar Disorders

4. Dysthymic Disorder

1. Depression

The term depression can in itself be misleading. Everyone in the normal course of daily life will experience alterations in mood. Depressed mood in this context does not represent a disorder or illness.
Sometimes, clinical depression may present in a mild form, so it is important to differentiate this from normal unhappiness.

2. Mania

If the mood becomes elated or irritable, this may be a symptom of mania. The term mania is used to describe severe cases, frequently associated with psychotic symptoms.
Hypomania describes a less severe form of the disorder. In clinical practice, this distinction often becomes blurred, with hypomania being seen as patients develop, or recover from, mania

3. Bipolar and unipolar disorders

Bipolar Disorders: In this case, the patient develops one or more severe episodes of a mood disorder which includes a manic episode. The existence of repeated manic episodes alone is sufficient to be termed a bipolar disorder
Two major types of bipolar disorders

• Bipolar I
• Bipolar II

Other types

• Rapid cycling
• Cyclothymic disorder

1. Bipolar I
   Full blown episodes of mania occurs here.
2. Bipolar II
   Depressive episodes are interspersed with less severe hypomanic episodes.
3. Rapid cycling
   The existence of four or more episodes within a year (i.e. Four depressive, manic, hypomanic, or mixed episodes within a 12-month period)
4. Cyclothymic disorder
   At least a 2 yr history of multiple episodes of hypomania & depressive symptoms.  These patients have never met full criteria for a major depressive or manic episode

A unipolar mood disorder is used to describe single episodes of depression

4. Dysthymic Disorder

This is a chronic depressed mood that does not meet the criteria for major depression.

Epidemiology

Differences in diagnosis (particularly of depression) make it difficult to estimate the true incidence of affective disorders.
Lifetime risk of developing a:

• Bipolar I disorder is about 1%
• Bipolar II disorder: 0.2% – 10.9%
• The incidence of bipolar I is generally reported to be the same for both men & women
• Bipolar II is slightly more common in women
• Also higher rates of depression are consistently found in women
• Depression may occur at any age, including early childhood
• Average age of onset of depression: mid 20s
• Incidence& prevalence of depression in women peaks at the age of 35 – 45 years

Aetiology

Like most psychiatric disorders, the causes of affective disorders remain unknown
Possible causes of it include the following:

• Genetic
• Environmental
• Biochemical
• Endocrine
• Physical illness and side effects of some medications

Genetic causes

• There is evidence of a genetic link
• Incidence of affective disorder in 1st degree relatives ofsomeone with severe depression: About 20%
• Four times greater risk of affective disorder in the children of both parents with an affective disorder
• The risk is doubled in children with one parent with an affective disorder
• Evidence of a genetic link has also been found in studies of children from parents with affective disorder who were adopted by healthy parents

• Environmental factors

Environmental stresses can often be identified prior to an episode of mania or , a causal depression. However relationship between a major event in someone’s life and the development of an affective disorder has not been firmly established. Employment higher socio-economic status & the existence of a close confiding relationship have been noted to offer some protection against the development of an episode

Biochemical factors

• Postulates a deficiency of neurotransmitteramines in certain areas of the brain, majorly, noradrenaline (norepinephrine), serotonin (5hydroxytryptamine) & dopamine.
• Based on the findings that both monoamine oxidase inhibitors (MAOIs)& tricyclic antidepressants (TCAs) appeared to increase neurotransmitter amines, particularly noradrenaline, at important sites in the brain.
• Reduceddopaminergic activity in depressed patients and anoveractivity in mania

Endocrine factors

Some endocrine disorders such as hypothyroidism & Cushing’s syndrome have been associated with mood changes. Depressed people are commonly found to have increased cortisol levels. This finding has been used as the basis for the dexamethasone suppression test in depression.

Physical illness and side effects of some medications

Mood disorders, particularly depression, have been associated with several types of medication and a number of physical illnesses.
Drugs such as analgesics antidepressants, antihypertensives, anticonvulsants, opiatewithdrawal, amphetamine withdrawal, benzodiazepine withdrawal, antipsychotics, benzodiazepines, antiparkinsonism agents, steroids, oral contraceptives have at one point or the other being implicated in some cases.

Physical illness

Diabetes, multiple sclerosis, Addison’s disease, viral illness, neurological disorders, carcinoma, systemic lupus erythematosus, pernicious anaemia.

Clinical Manifestations

a. Depression

To meet the criteria for depression (major depressive disorders or clinical depression):

• Patients should experience five or more persistent symptoms for at least 2 weeks.
• At least one of the symptoms must be diminished interest/ pleasure OR depressed mood.
• Symptoms should impair social or occupational functioning and should not be related to a general medical condition or substance abuse.

More clinical manifestations

1. Depressed mood can also be irritable mood for children and adolescents.
2. Diminished interest or loss of pleasure in almost all activities (anhedonia).
3. Significant weight change or appetite disturbance (for children, this can be failure to achieve expected weight gain).
4. Sleep disturbance (insomnia or hypersomnia).
5. Psychomotor agitation or retardation.
6. Fatigue or loss of energy
7. Feelings of worthlessness
8. Diminished ability to think or concentrate; indecisiveness
9. Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide.

b. Bipolar Disorder

For bipolar disorders, a standardized diagnostic criteria vary.

• ICD 11: at least two mood episodes must occur, one of which must be manic or hypomanic.
• DSM-5: at least one episode of mania must have occurred for a diagnosis of bipolar I disorder to be made; depression may also occur but it is not essential.

Bipolar II disorder

Never had a full manic episode; at least one hypomanic episode and at least 1 major depressive episode.

c. Mania

• The mood is described as elated or irritable and the accompanying over activity is usually unproductive.
• This inhibition may result in excessive spending sprees, inappropriate sexual activity & other high-risk behaviours.
• Driving may be particularly dangerous.
• Manic people describe their thoughts as racing, with ideas rapidly changing from one topic to another.
• Speech may be very rapid with frequent punning & rhyming.
• Ideas may become grandiose with patients embarking on fantastic projects that lead nowhere & inevitably are left incomplete & disjointed.
• Clothing is usually flamboyant, & if make-up is worn, it is usually expensive & involves bright colours

Investigations

There is no universally accepted tests to confirm the presence of an affective disorder. However, these following techniques can be used.

 i) Beck Depression Inventory

• Self-reporting scale with 21 depressive symptoms
• Subject marks on a scale of 1-4 how severe the symptoms are
• A higher score indicates more severe depression

ii) Hamilton Depression Rating Scale

This is used by a health professional at the end of an interview to rate the severity of the depression.

iii) Dexamethasone Suppression Test

This test  involves administration of 1 mg of dexamethasone at 11 pm which is said to coincide with the low point of cortisol secretion. It would be expected that normally dexamethasone would suppress secretion of cortisol for about 24 hrs. Blood samples are taken the following day at 8 am, 4 pm & 11 pm. If it is found that serum cortisol levels are elevated between 9 and 24 hrs after administration of dexamethasone, then this is taken as a positive result. i.e. dexamethasone has failed to suppress normal cortisol secretion.

• The test has limited value in practice
• It is not specific to depression & other disorders may account for an apparent positive result
• A large proportion of depressed people may show a negative result with the test.

Treatment

Goals of treatment

1. To minimize the symptoms
2. To improve quality of life & social/occupational functioning
3. To prevent relapse & hospitalization
4. To minimize adverse effects of medications
5. To prevent suicide attempts or self-harm or harm to others.

Treatment Options

1. Psychotherapy
2. Electroconvulsive therapy (ECT)
3. Complementary or Alternative Treatments
4. Pharmacotherapy

1. Psychotherapy

Examples of this are Interpersonal Psychotherapy & Cognitive
Behavioural Therapy (CBT).

• This is commonly used with pharmacotherapy as most patients would need help & support to cope with depression.
• It takes a longer time to be effective but may be good for preventing relapse.
• For mild forms of depression, non-drug treatments are generally considered as the 1st line treatment.

2. Electroconvulsive therapy (ECT).

• May be considered after referral to a psychiatrist.
• Although it is said to have a faster onset of action, its effects are fairly short-lived & antidepressants are often required to prevent relapse
• Although considered safe, there are risks from the anaesthetic agents.
• Some patients suffer short-term memory loss following treatment.
• ECT is effective in about 90% of patients

ECT is indicated in patients with:

• i) life-threatening suicidal or homicidal psychotic depression
• ii) severely depressed patients for whom antidepressant agents are contraindicated
• iii) acutely psychotic depressions that have not responded to antipsychotic or antidepressant agents
• iv) severe acute mania who are life-threatening & fail to respond to antipsychotic drugs
• v) severe schizophrenic affective disorders when the patient’s condition maybe life-threatening & who fail to respond to psychotropic drugs
• vi) severe catatonic excitement when the patient has failed to respond to antipsychotic agents.
• The mechanism of action of the ECT is unknown
• Since seizures cause release of various neurotransmitters in the brain, & ECT causes seizures, this action is hypothetically related to its therapeutic effects
• ECT is generally given 3 times a week for a maximum of 12 treatments
• A common rule is to give beyond remission of symptoms

Adverse effects of ECT
Adverse effects associated with ECT include memory loss & post-ECT confusion, spine & long bones fracture during seizures (eliminated by the use of muscle relaxants prior to ECT).
Complications: laryngospasm, cardiac arrest (rare). Elevated Cerebrospinal Fluid (CSF) pressure is an absolute contraindication.

3. Complementary or Alternative treatments

• The alternative treatment involves the use of St. John’s Wort (Hypericum perforatum): for mild or moderately severe depression.  No evidence to support its use in severe depression. This May induce the metabolism of other drugs.

4. Pharmacotherapy

Medication therapy leads to a more rapid response than psychotherapy, but when discontinued there is a risk of withdrawal symptoms. In moderate and severe depression, pharmacological intervention is important. But this should never be considered in isolation from the social, cultural and environmental influences on the patient.
Non-drug treatments & antidepressant medication are not mutually exclusive. In some cases, it is preferable to use both in combination.
Drug Treatment 

• Tolerability is an important factor in the choice of drug.
• Any claim of overall superiority of one antidepressant overanother would be premature
• Limited evidence supports the notion that monoamine oxidase inhibitors (MAOIs) are less effective than tricyclic antidepressants (TCAs) in hospitalized inpatients.
• Overall, selective serotonin reuptake inhibitors (SSRIs) appearto be better tolerated than the TCAs.
• Although, limited evidence suggests that venlafaxine may be more effective than SSRIs in hospital inpatients.
• Generally speaking, older drugs have a poorer side effect & toxicity profilethan the more recently introduced agents.
• Antidepressants should be taken in adequate doses for some 4 – 6 weeks (& up to 12 weeks in older people) to achieve a full response • Following a single episode of depression, treatment should be continued for 6 months at the same dose at which the patient achieved remission, before attempting withdrawal.
• Withdrawal should be undertaken gradually.
• Abrupt withdrawal: GI symptoms, headache, giddiness, sweat, shaking, insomnia, extrapyramidal reactions with some SSRIs.
• In patients experiencing multiple episodes of depression, treatment should be continued for longer periods (2 years).
• Following successful treatment, antidepressants should be gradually reduced over a period of 4 weeks

Class of drugs to use

1. Tricyclic antidepressants (TCAs)
2. Monoamine oxidase inhibitors (MAOIs)
3. Selective serotonin reuptake inhibitors (SSRIs)
4. Other drugs

Tricyclic Antidepressants (TCAs)

Mechanism of action

• TCAs Block the re-uptake of noradrenaline and/or 5-HT following their release & action as neurotransmitters.
• They do this to a greater or lesser degree.
• TCAs also have effect at α-adrenergic, histamine & cholinergic receptors.

Classification of TCAs

1. Tertiary amines (the dimethylated derivatives) e.g. amitriptyline, doxepin, imipramine, trimipramine, clomipramine
2. Secondary amines (the monomethylated derivatives) e.g. nortriptyline, desipramine, protriptyline
3. The tertiary amines These are more potent inhibitors of 5-HT reuptake than the secondary amines. Generally more sedating than the secondary amines.

Indications

• TCAs are not usually indicated 1st line for the treatment of depression.
• May be considered for patients with a history of response to TCAs;patients refractory to other medications; patients with co-morbidities that might benefit from TCAs (e.g. neuropathic pain, migraines)
• Can be lethal in overdose & should not be used in patients withsuicidal ideations
• Should be avoided or used with caution in patients with cardiovascularconditions, closed-angle glaucoma, urinary retention, or severe prostate hypertrophy.

Adverse effects

• May differ, depending on affinity for α-adrenergic, cholinergic & histamine receptors
• Tertiary amine TCAs have higher risk of causing anticholinergic adverse effects, sedation, weight gain, & orthostatic hypotension than secondary amine TCAs
• Elderly patients may experience memory impairment & confusion due to the anticholinergic effects
• Anticholinergic delirium may be seen in overdose
• Other adverse effects: tachycardia, orthostatic hypotension (especially in overdose), decreased seizure threshold, sedation, falls, & sexual dysfunction.
• TCAs have a potential for causing serotonin syndrome when used in combination with other serotonergic agents.

Examples 
Imipramine

• Females tend to tolerate imipramine less well than males
• Tolerance may develop to some of the unpleasant side effects
• May be facilitated by starting with a lower dose & gradually increasing the dose over a week
• Toxic in overdose
• Only use in circumstances where intentional overdose can be prevented

Desipramine

• Imipramine is metabolized by demethylation to an active metabolite, desipramine
• Both imipramine & desipramine have long half lifes that permit single daily dosing.

Amitriptyline

• Similar poor side effect & toxicity profile to imipramine but is moresedative
• Additional sedative properties may be beneficial for some selected patients

Nortriptyline

• The active metabolite of amitriptyline
• Both the parent drug & metabolite have long half lifes

Doxepin
Limited evidence suggests that it may have fewer cardiac effects in patients with pre-existing cardiac disease than other traditional TCAs
Clomipramine

• A potent 5-HT reuptake inhibitor
• Of value in obsessional states, in addition to its antidepressant effect
• Off-label use: premature ejaculation

Trimipramine

• A particularly sedative TCA with few differences from other TCAs

Other TCAs

• Amoxapine: a secondary amine
• Dosulepin: a tertiary amine
• Lofepramine: a tertiary amine

2. Monoamine Oxidase Inhibitors

Mechanism of Action

Inhibit monoamine oxidase (MAO) which is responsible for the breakdown of neurotransmitters e.g. dopamine, 5-HT, noradrenaline
Two forms of MAO exist:

1. MAO-A
2. MAO-B

• The inhibition of MAO-A is thought to be responsible for the anti depressant effects
• It is also responsible for metabolizing tyramine & producing the cheeseinteraction (Tyramine is metabolized by both forms of the enzyme)

Types of MAOI

1. The traditional MAOIs• Both non-selective & irreversible
   This is not widely prescribed. e.g. tranylcypromine, phenelzine
2. Selective reversible inhibitor of monoamine oxidase type A (RIMA). e.g. Mobeclomide

Due to the numerous adverse effects of MAOIs & their potential for drug-food interactions, they are only indicated in patients refractory to other antidepressants. MAOIs should only be considered when a 1st-line SSRI has failed. They are generally less effective & more toxic than the TCAs. However, they do not cause marked anticholinergic effects or cardiotoxic effectsassociated with TCAs.

Adverse Effects

• Hypertensive crises
• Can occur with increased levels of sympathetic amines (e.g. noradrenaline), possible through ingestion of tyramine-containing foods or administration of sympathomimetic agents (e.g. decongestants)
• Serotonin syndrome, orthostatic hypotension, peripheral oedema, weight gain, insomnia, sexual dysfunction (anorgasmia, decreased libido, erectile/ejaculatory dysfunction)
• MAOIs in combination with SSRIs, TCAs, serotonin & norepinephrine reuptake inhibitors, & any other agent with serotonergic activity can lead to serotonin syndrome
• The MAOIs are chemically related to the amphetamines
• Exhibit certain degree of CNS stimulation e.g. euphoria, increased wakefulness, restlessness

3. Selective Serotonin Re-uptake Inhibitors

Mechanism of Action

• SSRIs Block the re-uptake of 5-HT
• They do this to a greater or lesser degree

Facts about SSRIs

• SSRIs are considered to be the 1st line antidepressants for the treatment of depression
• They were developed to reduce some of the problems associated with the TCAs
• They appear to be better tolerated by patients, though they still cause some GIT side effects & sexual dysfunction.

Examples with features

1. Paroxetine –  This is more commonly implicated with extrapyramidal-type movements
2. Sertraline & Citalopram – Reduced propensity for interactions with drugs metabolized by CYP450 2D6 isoenzymes
3. Escitalopram – Theoretically, its use is on the basis that the R-enantiomer has no antidepressant effect, & may even counteract some of the antidepressant effects of escitalopram
4. Fluoxetine – Main difference with the other SSRIs is the long half-life of fluoxetine, & its primary active metabolite, desmethylfluoxetine. This long half life is a problem if severe side effects develop
5. Fluvoxamine

Side effects

Generally, the SSRIs are associated with: nausea, vomiting, insomnia, sedation, sexual dysfunction, headache, falls, akathisia, agitation & tremor

4. Other Drugs

• Lithium
• Trazodone
• Mianserin
• Serotonin-noradrenaline reuptake inhibitors (SNRIs).  This inhibit the re-uptake of 5-HT & NE. It has similar mechanism with the TCAs. It was hoped that they would have similar efficacy to TCAs but without their side effects. They can cause cardiac events & toxicity. Not recommended as a 1st or 2nd line treatment for most patients. Examples of this include venlafaxine, desvenlafaxine, duloxetine
• Reboxetine – A specific noradrenergic (norepinephrinergic) re-uptake inhibitor (NARI). Patients experiencing problems with serotonergic-related side effectsmay benefit from a switch to reboxetine
• Mirtazapine – A noradrenergic & specific serotonergic antidepressant (NaSSA) –  antagonizes α-adrenergic & 5HT2- and 5HT3-receptors, causing an increase in norepinephrine & 5-HT. Adverse effects: sedation, weight gain, constipation, dry mouth, increased appetite
• Bupropion
• Nefazodone
• Atypical antipsychotics e.g. olanzapine, quetiapine, aripiprazole.

Treatment options in pregnancy

• In pregnancy, benefit needs to be weighed against the risk of toxicity
• SSRIs & ECT are recommended treatment options
• Antidepressants are considered compatible with breastfeeding,but mothers should be warned of possible risks to their newborn
• Paroxetine – Pregnancy Category D due to cardiac malformations
• Bupropion – Pregnancy Category B.