Overview
In general, anti-depressants increase the availability of 5-HT and other monoamines AND normalize receptor density (they do not upregulate post and pre-synaptic receptors). The most commonly used antidepressants are SSRIs as they are relatively well tolerated. TCAs have fallen out of favour because they are very deadly in case of overdose (cause arrhythmia and refractory hypotension), but are still used in certain circumstances. MAOIs are only ever used as second-line options in resistant depression (which causes hypertensive crisis).
- Monoamine-Catecholamine theory (1965)
- Depression is caused by Decreased Monoamines (NA, 5-HT) both in the Central and Peripheral Nervous System (thus the somatic features – increased pain perception in depression)
- Reserpine was an anti-hypertensive drug that was shown to induce depression by rapidly depleting Noradrenaline.
- Indications for antidepressants
- Mood disorders
- Impulsivity (associated with personality disorders – BPD)
- Alcohol and Drug withdrawal symptoms
- Pain syndromes
- Nocturnal enuresis
- Narcolepsy
- Eating disorders
- Schizoaffective disorders
- Anxiety and related disorders (GAD, OCD, PTSD etc. )
Phases of treatment with antidepressants
| Phase | Duration |
|---|---|
| Acute phase | 3 months |
| Continuation phase | 6-12 months |
| Maintenance | Years |
Timeline of effects of antidepresants
| Effect | Timeline |
|---|---|
| Onset of action | 10 – 14 days |
| Maximum effects | 4 – 6 qeeks |
| Maintenance | 4 month to years (until symptom free) |
Classes of Antidepressants
| Class | Examples | Nota bene |
|---|---|---|
| Tricyclic antidepressants (TCAs) | amitryptiline (Elavil), clomipramine (Anafranil), imipramine (Tofranil) | Cheap, widely used, more side effects |
| Selective Serotonin Reuptake Inhibitors (SSRIs) | citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil) | Readily available but costly |
| Monoamine Oxidase Inhibitors (MAOIs) | phenelzine (A and B), selegiline (B) | Not available locally (Kenya), reserved for resistant depression |
| Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) | venlafaxine (Effexor), desvenlafaxine (Pristiq), duloxetine | Readily available, costly |
| Serotonin antagonists and reuptake inhibitors (SARIs) | trazodone (Desyrel) | Not readily available, costly |
| Norepinephrine and Dopamine Reuptake Inhibitors (NDRIs) | buproprion (Wellbutrin) | Quite stimulating, readily available |
| Noradrenergic Reuptake Inhibitors (NaRIs) | raboxetine (Remeron) | Very stimulating |
| Noradrenergic and specific serotonergic antidepressants (NaSSAs) | mirtazapine (Remeron) | Readily available but costly |
Tricyclic Antidepressants (TCAs)
TCAs block reuptake of monoamine neurotransmitters (NA, 5-HT). Side-effect profile is due to histaminergic, alpha-adrenergic, and muscarinic receptor blockade.
TCAs were the original therapy for depression but have since fallen out of favor to SSRIs. They are cheaper than SSRIs, have more side-effects, but are still widely used. They have a high mortality and are deadly in case of overdose (causes arrhythmia and have a low therapeutic window; remember that patients with MDD are at risk of suicide and may overdose on their prescription). Assess the patient for suicidality and don’t give more than 2 week supply.
Examples: clomipramine, imipramine, amitryptiline
Oral and Parenteral Formulations are available
Classification of TCAs
| Classification | Description |
|---|---|
| Tertiary amines (amitryptiline, imipramine, clomipramine) | 5-HT > NA, Binds more receptors, more sedating (high antimuscarinic and antihistaminic activity), antiadrenargic with a greater lethality in overdose |
| Secondary amines (desipramine, nortriptyline) | NE > 5-HT, fewer adverse effects (less antimuscarinic/antihistaminic/antiadrenergic) |
Selected TCAs and their uses
| TCA | Other uses |
|---|---|
| Amitryptiline | Chronic pain, migraine, insomnia |
| Clomipramine | OCD (since it is the most serotonin-specific) |
| Doxepin | Chronic pain, sleep aid in lower doses |
| Nortriptyline | Chronic pain |
Classification of TCAs according to their sedative effect
| Classification | Examples |
|---|---|
| More sedative | Amitriptyline, clomipramine, dosulepin, trazodone |
| Less sedative | Imipramine, lofepramine, nortriptyline |
- Apart from Major Depressive Disorder, which other disorders can TCAs be prescribed (as second-line)
- Obsessive Compulsive Disorder (OCD): First line is Fluvoxamine (SSRI, Luvox); Second line is Clomipramine (TCA)
- Enuresis: First line is Desmopressin (DDAVP), Second-line is Imipramine (TCA)
- Pain disorders, neuropathy: First line is gabapentin or pregabalin, second-line is Amitryptiline (TCA)
- What should you consider when prescribing TCAs?
- Start low: to avoid toxicity; takes weeks for effects to show. Using high-doses WILL NOT LEAD TO FASTER ONSET OF ACTION)
- Drug selection: “Choose your side-effects: Give sedating drugs to patient with insomnia at night (imipramine, amitryptiline )
- Patient and family psychoeducation: 2-4 week delay in therapeutic effect is anticipated. Admit patient if there is a high-risk of suicide.
- Adverse effects of TCAs
- Orthostatic hypotension (most common cause of death in overdose)
- Anti-cholinergic symptoms: constipation, xerostomia, xeropthalmia, bradycardia etc.
- Used in suicide attempt (Overdose)
- Cardiac conduction changes: Arrhythmia
- Allergic effects: Photophobia, jaundice
- CNS effects: Sedation, Myoclonic toitelieus, Tremors, Seizures
- Endocrine effects: Weight gain, elevated blood sugar (Histaminergic properties)
- Sexual dysfunction (anticholinergic and antiadrenergic)
- Psychiatric effects: causes a switch to mania; 50% of BP1D patients;1-7% of patients with unipolar depression… indicating a misdiagnosis)
- Acute intoxication (Overdose)
- CNS effects: excitement, hallucination, delirium, convulsions, respiratory depression, coma
- CVS effects: Cardiac dysrhythmia → Ventricular Fibrillation → Sudden death
- Refractory hypotension is the most common cause of death in overdose
Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs are by far the safest AND treatment of choice for Major Depressive Disorder and other mood disorders with significant depressive symptoms. They are very very well tolerated but quite costly. They are the most prescribed antidepressants in the developed world. Take 2-3 weeks for effects to show but side-effects may manifest on the same day.
Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertaline, Vortioxetine, Vitazodine
Some selected SSRIs
| SSRI | Nota Bene |
|---|---|
| Fluoxetine | Has the longest half-life (15 days). Active metabolite is norfluoxetine (6 week washout period). Watch out for SIADH and extrapyramidal symptoms (increases concentration of antipsychotics). Administer in the morning due to insomnia. High dose fluoxetine (60mg) can be used for bulimia nervosa |
| Paroxetine | Has the shortest half-life (rarely used, more likely to cause SSRI discontinuation syndrome). Has anticholinergic adverse effects. No metabolite |
| Sertraline | Needs to be taken with food. Also has dopaminergic activity. Watch out for extrapyramidal symptoms. No active metabolite. Low drug interactions. |
| Citalopram | Fewest drug-drug interactions. Can cause dose-dependent QT prolongation. |
| Escitalopram | This is a levo-enantiomer of citalopram (has fewer side effects). Can also cause dose-dependent QT prolongation |
| Fluvoxamine | Currently approved for obsessive-compulsive disorder (OCD). Has multiple drug interactions since it inhibits CYP |
- Other disorders appart from depression treated using SSRIs
- Anxiety disorders (Long-term; Benzodiazepines are used for acute care)
- Panic Disorder
- Generalized Anxiety Disorder (GAD)
- Social Anxiety Disorder (SAD)
- **Obsessive Compulsive Disorder (**OCD)
- Bulimia Nervosa (Patient with an eating disorder + normal weight)
- Anorexia Nervosa (Pt with an eating disorder + weight loss)
- Gambling Disorder
- **Post-Traumatic Stress Disorder (**PTSD)
- Insomnia
- Anxiety disorders (Long-term; Benzodiazepines are used for acute care)
- Adverse effects of SSRIs
- Sedation (Increases availability of Serotonin)
- Reduction of appetite → weight loss
- **Sexual dysfunction (**especially in men, causes delayed ejaculation and loss of libido)
- Diarrhea, Nausea, Vomiting, Abdominal Pain
- Akathisia (Restlessness, and EPS)
- Anxiety (or agitation, during early treatment then clears eventually)
- Insomnia and fatigue (very common, dosed in the morning)
- Serotonin syndrome (mild features of NMS, occurs in very high doses of SSRIs, SSRI + SSRI or SSRI + MAOi)- NMS excitability, AMS, Autonomc dysfunction. Treated with benzodiazepines or cyproheptadine if benzodiazepines are ineffective.
- Drug-drug interactions of SSRIs
- NSAIDs and aspirin: if SSRIs are given with NSAIDs they should be combined with a PPI
- Warfarin/heparin: avoid SSRIs and consider mirtazapine
- Triptans: avoid SSRIs
- Which antidepressant is used to replace SSRIs if significant sexual dysfunction?
- Bupropion (Wellbutrin)
- Which SSRIs are preferred in patients with multiple comorbid conditions?
- Escitalopram and Sertraline (have very few drug interactions)
- Also helpful for anxiety associated with depression
- Why is sexual dysfunction more of an issue in men who are on SSRIs?
- Differences in how men need to function sexually
- Men need to obtain an erection to perform sexual function
- Visible orgasm in men
- Men are more likely to have anxiety surrounding their sexual performance
- Differences in how men need to function sexually
Monoamine Oxidase Inhibitors (MAOIs)
MAOIs increase the cytoplasmic pool of Monoamines causing spontaneous leakage into the synaptic cleft (by inhibiting MAO in the pre-synapse). They are not readily available locally and are reserved for resistant depression. MAOIs are rarely used due to their significant adverse effects (Hypertensive crisis) when taken in large amounts OR in combination with tyrosine-rich foods/meds (Sympathomimetics -stimulants, asthma meds; nuts, aged cheese)
Selegeline (B), Phenlezine (A and B), Rasagiline
- Why are non-depressed individuals at risk of abusing MAOIs?
- Causes euphoria and excitement in non-depressed individuals
- Which MAOI is also used in neurology (Parkinson’s) to increase dopamine availability?
- Selegiline
- Adverse effects of MAOIs
- Hypotension
- Hypertension
- Hypertensive crisis (d/t food and drug interactions
- Food interactions: aged cheese, red wine, over-ripe fruits, beer, yoghurt, bananas, sausage, nuts
- Drug interactions: Pseudoephedrine, Dextromethorphan, Salbutamol
- CNS effects: Tremors, Excitement, Insomnia, Convulsions
- Weight gain (Increases appetite)
- Severe hepatotoxicity (Rare)
Other antidepressants
NDRI: Buproprion has minimal sexual side effects and is activating. Only downside is that INCREASES THE RISK OF SEIZURES.
SNRIs: Venflafaxine is also activating and can be used as Buproprion. Does not increase the risk of seizures. It is more effective and offers better remission than SSRIs. Duloxetine should be avoided in renal failure
SARIs: Trazodone is highly sedating
NaSSA: Mirtazapine increases appetite and weight and has a faster onset of action (Unlike other SSRIs). It is quite sedating. Useful for comorbid alcohol use disorder and depression (J Dual Diag 2012;8(3):200)
NARi: Raboxetine ****is very stimulating and is used as prophylaxis and treatment of severe depression
- Which groups of patients with depression do we prefer to use Buproprion/ Venlafaxine?
- Which groups of patients with depression do we avoid using Buproprion?
- Patients with recent seizures
- Patients with a history of epilepsy
- Which group of patients with depression do we prefer to use Venlafaxine?
- Patients with sexual side effects (previously on SSRIs)
- Patients with hypersomnia (additionally blocks the reuptake of Norepinephrine)
- Which group of patients with depression do we prefer to use Duloxetine?
- Patients with peripheral neuropathic pain and diabetes
- Which group of patients with depression do we prefer to use Trazodone?
- Patients with significant insomnia and anxiety
- Which group of patients with depression do we prefer to use Mirtazapine?
- Older patient (Loss of appetite as a symptom of depression)
- Underweight patient (Loss of appetite as a symptom of depression)
- Severely depressed patient (due to faster onset of action)
Other drugs used for Depression
Agomelatine(valdoxan): used for seasonal depression
Esketamine: shows very good results in severe refractory depression
Atypical antipsychotics: olanzapine, aripiprazole, brexpiprazole and quetiapine have been approved as adjuvants in depression with psychotic features and severe depression with suicidal ideation (especially Clozapine)
Lithium: given as an adjuvant to reduce the risk of suicide. An advantage is that it is also safe in case of overdose.
- Others
- Levothyroxine, Liothyronine
- Pindolol
- Gingseng
- St. John’s Wort
- Buspirone (Buspan)
Switching antidepressants
- Switching from citalopram, escitalopram, sertraline or paroxetine
- Withdraw the first SSRI (gradually reduce the dose then stop) before starting the alternative SSRI
- Switching from fluoxetine to another SSRI
- Withdraw then leave a gap of 4-7 days before starting a low-dose of the alternate SSRI. This is because fluoxetine has a long half-life
- Switching from an SSRI to a TCA
- Cross-tapering is recommended (reduce the current SSRI dose slowly while increase the slowly increasing the dose of the TCA)
- The exception if fluoxetine which should be withdrawn before startin a TCA
- Switching from citalopram, escitalopram, sertraline or paroxetine to venlafaxine
- Cross-taper cautiously. Can start venlafaxine 37.5 mg daily and increase very slowly
- Switching from fluoxetine to venlafaxine
- Withdraw fluoxetin and then start venflafaxine at 37.5 mg daily and increase very slowly
Antidepressant discontinuation syndrome
Antidepressant discontinuation syndrome follows abrupt cessation or discontinuation of antidepressant after being taken continuously for one month
- Signs and symptoms of antidepressant discontinuation syndrome (FINISH)
- Fatigue, lethargy
- Insomnia (with vivid dreams or nightmares)
- Nausea/Vomiting
- Imbalance (dizziness, vertigo, light-headedness)
- Sensory disturbances (”burning”, “tingling”, “electric”, “shock”)
- Hyperarousal (anxiety, irritability, agitation, aggression, mania, jerkiness)
- How to differentiate antidepressant discontinuation syndrome from relapse (depression/anxiety)
- Symptoms of relapse usually take more than a few days to appear
- Symptoms of relapse disappear following reintroduction of the antidepressant