Major Depressive Disorder: Pharmacotherapy

Table 1. Prescribing Information of Antidepressants used in MDD[1,5,6,8,11,13,19]

Please refer to the Healthier SG whitelist for the full list of subsidised drugs.

Selective serotonin reuptake inhibitor (SSRI)

Medication	Initial Daily Dose (mg)	Maintenance Daily Dose Range (mg)	Max Daily Dose (mg)	Relevant Characteristics	Side Effects		Special Precautions		Drug Interactions
FLUOXETINE	10 – 20 (Note: Fluoxetine is available in capsule form, which means it cannot be split or halved; doses should be adjusted using the appropriate capsule strength.)	20 - 60	80	Activating Lower treatment drop-out due to side effects Long half-life therefore less risk of discontinuation symptoms Suitable for patients with poor medication adherence due to long half-life Nonlinear elimination kinetics and hence safer in overdose	Common across all SSRIs Gastrointestinal: nausea, abdominal pain, diarrhoea, constipation, weight loss Autonomic: agitation, tremor, akathisia, insomnia Sexual dysfunction	Anxiety, agitation Delayed ejaculation/orgasmic impotence Insomnia common and hypersomnolence (at high doses) Nausea Dry mouth	Common across all SSRIs For patients with renal and hepatic impairment, adjust dose as indicated Risk of bleeding abnormalities with SSRIs; bleeding tendency may be increased if concurrently used with anticoagulants, or medications that affect platelet function (e.g. NSAIDs and aspirin). Use with caution in patients with glaucoma as SSRIs may raise intraocular pressure Contraindicated with patients on monoamine oxidase inhibitor (MAOI) or within 14 days of stopping MAOI Can cause hyponatremia (higher risk in patients on diuretics) Watch out for emergent hypomania/mania after anti-depressant use and discontinue if occurs Elderly: Associated with bone loss and fractures	Long half-life and hence greater difficulty in switching to another antidepressant Elderly: Long elimination half-life may require dose adjustment to reduce the risk of accumulation Avoid in patients taking tamoxifen as it is a potent inhibitor of CYP2D6, which may reduce the effectiveness of tamoxifen in treating breast cancer.	Washout period before taking MAOI: 5 weeks Consider drug interactions with medications metabolised extensively by CYP450 enzymes 1A2, 2C19, 2D6, and 3A4 Inhibition of P450 CYP2D6 may elevate concentration of other drugs (especially those with narrow therapeutic index): flecainide, quinidine, carbamazepine, TCAs
FLUVOXAMINE	25 - 50	50 - 200	300	Sedating Highly selective SSRI Much shorter elimination half-life compared to other SSRIs		Nausea (more common than other SSRIs) Sexual side effects (similar to other SSRIs) Minimal effects on psychomotor and cognitive function			Consider drug interactions with medications metabolised extensively by CYP450 enzymes 1A2, 2C19, 2D6, and 3A4 Strong inhibitor of CYP1A2, CYP2C19, and CYP3A4
SERTRALINE	25 - 50	50 - 150	200	Preferred for pregnant and breastfeeding women Preferred in patients with heart disease (myocardial infarction & heart failure) Preferred for breast cancer patients on tamoxifen, as it is a less potent inhibitor of CYP2D6 Activating Dose adjustment not routinely required in renal insufficiency		Gastrointestinal disturbance (27%) Headache (26%) Insomnia (22%) Dry mouth (15%) Ejaculation failure (14%)		Contraindicated in breast cancer patients receiving tamoxifen as it will inhibit metabolism of tamoxifen	Less likely to cause CYP450-related drug interactions as it is a weak inhibitor
ESCITALOPRAM	5 - 10	10 - 20	20	Most selective SSRI Fewer side effects, more potent, shorter half-life Lower treatment drop-out due to side effects Preferred for breast cancer patients on tamoxifen, as it is a less potent inhibitor of CYP2D6, unlike fluoxetine and paroxetine		Greater propensity for weight gain Nausea and vomiting (20%) Increased sweating (18%) Dry mouth and headache (17%) Anorgasmia and ejaculatory failure No significant effect on cardiac conduction and repolarisation		Dose-dependent QTc prolongation (higher risk than other SSRIs, but lower risk than antipsychotics)	Relatively weak inhibition of liver P450 enzymes Less drug-drug interactions
PAROXETINE	Immediate Release 10-20 Controlled Release 12.5	Immediate Release 20-40 Controlled Release 25 - 50	Immediate Release 60 Controlled Release 62.5	Most sedative and anticholinergic SSRI Preferred for breastfeeding women Discontinuation symptoms may be more common & significant due to short half-life. Minimised with use of controlled release formulation		Anticholinergic side effects Greater propensity for weight gain Nausea Sexual side effects: dose-dependent Closed angle glaucoma (acute) Increased risk of serious congenital (particularly cardiac) defects in utero: first-trimester use should be avoided		Risk of foetal exposure resulting in pulmonary hypertension Avoid in patients taking tamoxifen as it is a potent inhibitor of CYP2D6, which may reduce the effectiveness of tamoxifen in treating breast cancer	Clinically significant interaction: MAOI, TCA, Type 1C antiarrhythmics Probably significant interaction: β-adrenergic antagonists, antiepileptic agents, cimetidine, typical antipsychotics, warfarin Consider drug interactions with medications metabolised extensively by CYP450 enzymes 1A2, 2C19, 2D6, and 3A4 Strong inhibitor of CYP2D6; contraindicated for concurrent use with CYP2D6 substrates that can prolong QT interval

Serotonin-norepinephrine reuptake inhibitor (SNRI)

Medication

Initial Daily Dose (mg)

Maintenance Daily Dose Range (mg)

Max Daily Dose (mg)

Relevant Characteristics

Side Effects

Special Precautions

Drug Interactions

VENLAFAXINE

Immediate Release

37.5-75

Controlled Release

75

Immediate Release

75 – 225

Controlled Release

75 - 150

Immediate Release

375

Controlled Release

225

More rapid onset action and enhanced efficacy in severe depression

Insomnia very common

Nausea (35%)

Sustained hypertension (dose-related, 50% remits spontaneously)

Dry mouth

Constipation

Sexual dysfunction

Common across all SNRIs

Can raise intraocular pressure and precipitate glaucoma, i.e. acute angle closure glaucoma

Can cause hyponatremia

(higher risk in patients on diuretics)

Watch out for emergent hypomania/mania after anti-depressant use and discontinue if occurs

Risk of bleeding abnormalities with SNRIs; bleeding tendency may be increased if concurrently used with anticoagulants, or medications that affect platelet function (e.g. NSAIDs and aspirin)

Elderly: Associated with bone loss and fractures

Caution in patients with severe or poorly controlled hypertension. Consider monitoring blood pressure frequently during initiation

Adjust dose in patients with renal and hepatic impairment

Venlafaxine with cimetidine raises the risk of high blood pressure or liver disease and should be avoided

Discontinuation syndrome more prominent

Less likely to cause CYP450-related drug interactions as it is a weak inhibitor.

Contraindication: Concomitant use or within 14 days of discontinuing therapy with MAOIs.

DULOXETINE

30

60 - 90

120

Useful for patients with chronic pain and fibromyalgia

Nausea, dry mouth, dizziness, headache, somnolence, constipation, fatigue

Small but significant increase in heart rate

Low rate of sexual dysfunction

May cause increased blood pressure and is contraindicated in patients with uncontrolled hypertension

Contraindicated if substantial alcohol use is present, if severe renal impairment (creatinine clearance

<30 ml/min) is present, or if liver disease is present

Higher risk of discontinuation symptoms

Contraindication: Concomitant use or within 14 days of discontinuing therapy with MAOIs.

Consider drug interactions with medications metabolised extensively by CYP450 enzymes 1A2, 2C19, 2D6, and 3A4

Contraindicated for concurrent use with strong CYP1A2 inhibitors (such as ciprofloxacin and fluvoxamine)

Noradrenergic and specific serotonergic antidepressant (NaSSA)

Medication

Initial Daily Dose (mg)

Maintenance Daily Dose Range (mg)

Max Daily Dose (mg)

Relevant Characteristics

Side Effects

Special Precautions

Drug Interactions

MIRTAZAPINE

7.5 - 15

15 - 45

45

Sedating at lower doses and activating at higher doses

Lower risk of hyponatremia

No effects on seizure threshold or on cardiovascular system

Suitable for patients who cannot tolerate SSRI/SNRI-induced sexual dysfunction

Drowsiness

Weight gain

Increased appetite

Dry mouth

Postural hypotension

Greater propensity for anticholinergic effects

Greater propensity for weight gain

Watch out for emergent hypomania/mania after antidepressant use and discontinue if occurs

Melatonergic Agonist and Serotonergic Antagonist antidepressant (Melatonergic Antidepressant)

Medication

Initial Daily Dose (mg)

Maintenance Daily Dose Range (mg)

Max Daily Dose (mg)

Relevant Characteristics

Side Effects

Special Precautions

Drug Interactions

AGOMELATINE

25

Monitoring

Monitor LFT at baseline, then after 3, 6, 12 and 24 weeks of therapy, and thereafter when clinically indicated

Repeat monitoring at the same frequency as when initiating treatment if the dose is increased

Consider annual monitoring of LFT for patients on longer-term maintenance therapy, after initial monitoring

25-50

50

Sedating effect. Sleep-modulating effects may be helpful with sleep

Lower treatment drop-out due to side effects, compared to other antidepressants

Lower propensity to cause sexual dysfunction compared to SSRIs and SNRIs

No discontinuation symptoms; no dosage tapering is needed on discontinuation

Lower risk of antidepressant-induced hyponatremia

Common

Hyperhidrosis, nausea, vomiting, diarrhoea, constipation, somnolence, headache, back pain, insomnia, abnormal dreams/ nightmares, raised liver enzymes

Significant

Increased liver enzymes >10 X ULN

Contraindications

Hepatic impairment (cirrhosis or active liver disease)

Transaminitis >3 X ULN

Concomitant use with strong CYP1A2 inhibitors. (e.g., fluvoxamine, ciprofloxacin)

Increased risk of hepatotoxicity with alcohol

Precautions

Mild transaminase elevation (≤3 X ULN)

Risk factors for hepatic injury (e.g., obesity, diabetes mellitus, excessive alcohol consumption, alcoholism)

Concomitant use of medications associated with risk of hepatic injury

Smokers (particularly those who smoke ≥15 cigarettes/day)

Moderate to severe renal impairment

Avoid use in the elderly ≥75 years (due to lack of efficacy)

Avoid use in the elderly with dementia (due to lack of data on safety and efficacy)

Watch out for emergent hypomania/mania after antidepressant use and discontinue if it occurs

Substrate of CYP1A2, CYP2C9 and CYP2C19; hence, inhibitors may reduce agomelatine clearance and lead to increased levels

Strong CYP1A2 inhibitors: (e.g., fluvoxamine, ciprofloxacin)

Moderate CYP1A2 inhibitors: (e.g., estrogens, propranolol, enoxacin)

CYP1A2 inducers (e.g., rifampicin) may reduce agomelatine bioavailability

Smoking induces CYP1A2 and has been shown to decrease the bioavailability of agomelatine; dose adjustments might be necessary if smoking is started, modified or stopped during treatment.

Tricyclic antidepressant (TCA)

Medication	Initial Daily Dose (mg)	Maintenance Daily Dose Range (mg)	Max Daily Dose (mg)	Relevant Characteristics	Side Effects	Special Precautions	Drug Interactions
AMITRIPTYLINE	10 - 25	50 - 100	100	Not first-line treatment due to potential cardiotoxicity in overdose Sedating Useful for those with migraine and chronic pain	Anticholinergic (e.g., constipation, blurred vision, urinary retention, dry mouth, dizziness, syncope, postural hypotension, sedation) Histaminergic and dopaminergic blockade: nausea, vomiting, weight gain, sedation Increased intra-ocular pressure Sexual dysfunction Hyponatraemia Cardiac: arrhythmias, ECG changes (QTc prolongation), tachycardia, palpitations, heart block Overdose may lead to delayed ventricular conduction time, dilated pupils and acidaemia due to central respiratory depression and fall in pH reducing protein binding Use with caution in patients with hepatic or renal dysfunction and in elderly patients	Contraindications Cardiac diseases (e.g., acute recovery post myocardial infarction, acute heart failure, arrhythmias) Epilepsy (lower seizure threshold) Severe liver disease Prostatic hypertrophy Mania MAO inhibitors used within past 14 days Can cause hyponatremia Watch out for emergent hypomania/mania after anti-depressant use and discontinue if occurs	-
CLOMIPRAMINE	12.5-25	50-100 in divided doses (BD)	200	Not first-line treatment due to potential cardiotoxicity in overdose
IMIPRAMINE	25 - 50	50 - 150	150
NORTRIPTYLINE	10 - 25	50 - 100	100

Figure 1: Advice to Patients Starting on Antidepressants[19]

Figure 1. Advice to Patients Starting on Antidepressants¹⁹ (Source: 2025 MDD ACG)

Table 2: Phases of Pharmacotherapy[19]

Figure 2. Treatment Phases of MDD (adapted) (Source: 2025 MDD ACG)

Aim of Acute Phase: To restore function and resolve symptoms (since remission of symptoms is associated with reduced risk of relapse)

Aim of Maintenance Phase: To sustain remission and reduce risk of relapse

Acute Phase

1. Initiate typical starting doses (usually at lower dosages) and titrate based on the patients' response, tolerability, and adverse effects.

2. All antidepressants, once started, should be continued for at least 4 to 12 weeks to allow time for full effect before making adjustments.

3. Continue until the patient achieves remission of symptoms. This usually takes 6 to 16 weeks.^20,21

4. Full remission of symptoms may not always be viable for all patients, for example, those with persistent depression or with limited life expectancy. In such cases, treatment may focus on reducing depression symptoms or increasing quality of life as much as possible.

Maintenance Phase

1. Continuation of pharmacotherapy for an appropriate duration after achieving remission in the acute phase is necessary to prevent a relapse.

2. Continue antidepressants for at least 6 months after remission because relapse occurs most frequently during this time.

3. Maintain the same dose of antidepressant that achieved remission in the acute phase (optimal dose) during the maintenance phase.

4. After 6 months, utilise shared decision-making with patients regarding further continuation of antidepressants. Consider the following key factors (Figure 3) when making shared decisions with the patients.

Figure 3. Key considerations for continuing or discontinuing antidepressants after 6-month maintenance treatment (Source: 2025 MDD ACG)

5. Patients with risk factors for relapse (Table 3) should be considered for longer duration of treatment, up to 2 years or longer.

6. If a decision is made to discontinue antidepressant treatment, it should not be abruptly stopped but rather tapered off gradually (within weeks, or even months).^22,23 This is to minimise the development of discontinuation symptoms.^25,26 Slower tapering may be required in patients who have been on antidepressants for a longer duration. Antidepressants with a short half-life also need to be tapered more slowly.²⁵

7. Advise patients to monitor for discontinuation symptoms and potential increase in suicidality when antidepressants are discontinued, especially during the initial one month after stopping the antidepressant.²⁸

8. Antidepressant discontinuation symptoms can be summarised using the acronym FINISH:

a. Flu-like symptoms (lethargy, fatigue, headache, aches, sweating).
b. Insomnia (with vivid dreams or nightmares).
c. Nausea (vomiting may occur).
d. Imbalance (dizziness, light-headedness).
e. Sensory disturbances (“burning" or “tingling" sensations).
f. Hyperarousal (anxiety, irritability, agitation, aggression, mania).

9. Advise patients to monitor for symptoms of a relapse, so that treatment can be provided promptly.

Table 3: Risk Factors for MDD Relapse[19,21,22,27]

Clinical Picture and Family History
1	Persistent residual symptoms*
2	History of childhood maltreatment*
3	Greater severity of first MDD episode (high clinical severity, higher PHQ-9 scores, greater number of symptoms and presence of suicidality)
4	Chronic depressive episodes
5	Presence of medical comorbidities (psychiatric or nonpsychiatric)
6	Higher lifetime number of MDD episodes
7	Younger age at onset of the first MDD episode^
Psychological and Psychosocial Risk Factors for Relapse
8	Presence of rumination
9	Presence of cognitive biases^
10	Personalities with high neuroticism^
11	Persistent stressful life events
12	Poor social support

*These have robust evidence as risk factors for relapse

^Potential prognostic factors

Guidelines on Switching Antidepressants[1,29,30,31]

^{General Principles
1. When patients respond poorly to an antidepressant medication or experience intolerable side effects, GPs should consider switching to another antidepressant
2. The choice of switching strategy is influenced by the following:²⁹}

^{a. Reason for switch (e.g. unable to tolerate adverse effects, inadequate response)}
^{b. Characteristics of the medications involved (e.g. half-lives, risk of discontinuation symptoms, potential for drug-drug interactions, dose and duration of current treatment)}
^{c. Patient factors (e.g. sensitivity to adverse effects, risk of relapse, ability to understand and administer medication schedule, experience of previous switches)}

^{3. Switching Strategies (Table 4)}

^{a. Direct switching}
^{b. Taper and start}
^{c. Cross-tapering}

^{4. Abrupt withdrawal of antidepressants should be avoided to minimise discontinuation symptoms
5. Refer to Table 5 for suggested specific switching strategies between different classes of antidepressants. Please note that these are general guidelines, and GPs should consult relevant drug formularies or seek pharmacists' advice for specific medication advice.
6. The switching of antidepressants to and from MAOIs is not included in this section. GPs should refer to references cited in this anchorlink (References 1, 30 and 31) for further information. Switching to and from a MAOI can be complex, and if uncertain, GPs should consult specialist advice or refer patients to a specialist for management.}

Table 4. Switching Strategies

Strategy	Method	Advantages	Disadvantages
Direct Switch	May be appropriate when switching between antidepressants that share pharmacodynamic profiles, such as within the same drug class (e.g., SSRIs) or in similar classes (e.g., SSRIs and SNRIs). In a direct switch, the current antidepressant is stopped, and the new antidepressant is started the next day at the equivalent or lower dose.	Simple and easy to follow.	Despite similar mechanisms of action, patients who have taken antidepressant for at least 6 weeks may experience discontinuation symptoms when switched directly to another antidepressant. If the direct switch is due to a severe adverse reaction from the current antidepressant, wait a few days (e.g., 2 - 3 days) after stopping before starting the new antidepressant. Discontinuation symptoms resulting from stopping the current medication may be mistaken as adverse side effects of the new antidepressant. The new antidepressant should not be abruptly stopped.
Taper and Start	Safest. Most conservative strategy with the lowest risk of drug-drug interactions and additive adverse effects. After tapering, may include a washout period before starting the new antidepressant at a low dose. Especially used when switching patients to or from a MAOI.	Maximises safety and reduces the risk of drug-drug interactions, which can cause severe toxicity, including hypertensive crisis or serotonin syndrome. A shorter washout period of less than 2 weeks may be justified in specific urgent situations.	GPs should still switch with caution due to the risk of drug-drug interactions. Risk of discontinuation symptoms and relapse of depression during tapering and washout period.
Cross-tapering	The current antidepressant is gradually reduced (in absolute dose amount or dose percentage) to zero while the new antidepressant is simultaneously started and titrated up to the therapeutic range. Typically, cross-taper over 1 - 2 weeks but should be extended longer (e.g., 3 to 4 weeks) for patients sensitive to side effects or discontinuation symptoms.	Minimise drug-drug interactions. Prevent discontinuation and depressive symptoms from abrupt drug withdrawal.	Cross-tapering is contraindicated if patients are switched to or from a monoamine oxidase inhibitor (MAOI), or if the 2 antidepressants can cause significant drug-drug interactions.

Table 5. Specific Switching Between Antidepressants[f]

^hThe switching of antidepressants to and from MAOIs is not included in this section. GPs should refer to references cited in this anchorlink (References 1, 30 and 31) for further information. Switching to and from a MAOI can be complex and if uncertain, GPs should consult specialist advice or refer patients to a specialist for management. (See Paragraph 6)

+Fluoxetine may increase exposure to duloxetine and venlafaxine as it is a strong CYP2D6 inhibitor

*Fluvoxamine may increase exposure to duloxetine as a strong CYP1A2 inhibitor

#Paroxetine may increase exposure to duloxetine and venlafaxine as a strong CYP2D6 inhibitor

@Paroxetine, and fluoxetine (strong CYP2D6 inhibitors) may interact with duloxetine and venlafaxine

^Fluvoxamine (strong CYP1A2 inhibitor) may interact with duloxetine

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