Generalised Anxiety Disorder : Pharmacotherapy

Table 1. Prescribing Information of Medications used in GAD [2,6,8,11,12,20-25]

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%)			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 anti-depressant 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 antidepressants (TCAs)

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	150	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

Antihistamine

Medication

Main Indications

Initial Daily Dose (mg)

Maintenance Daily Dose Range (mg)

Max Daily Dose (mg)

Relevant Characteristics

Side Effects

Special Precautions

Drug Interactions

HYDROXYZINE

Adjunctive therapy for mild GAD

10 - 25

50-100 in divided doses. (ON to QDS)

Elderly: Lower doses may be necessary.

100

Elderly: 50

Sedating and non-addictive

Dizziness, Drowsiness, Headache, Dry mouth, Blurred vision, Constipation, Urinary retention

May prolong QT interval

Contraindicated during early pregnancy, prolonged QT interval, history of torsade de pointes, including congenital long QT syndromes; history of cardiac arrhythmias; significant electrolyte imbalance (eg, hypokalemia, hypomagnesemia); significant bradycardia; family history of sudden cardiac death; concomitant use with other QT/QTc-prolonging drugs or with CYP3A4/5 inhibitors; asthmatics who have previously experienced a serious anti-histamine induced adverse bronchopulmonary effect; porphyria

Anticholinergic effects are not well tolerated in the elderly.

Not recommended for use as a sedative or anxiolytic in the elderly.

May enhance the CNS depressant effects of other antihistamines, barbiturates, benzodiazepines, hypnotics, antidepressants, antiemetics, antiepileptics, skeletal muscle relaxants, sedatives, opioids, and anaesthetics.

Central and peripheral antimuscarinic side effects may be increased with TCAs, MAOIs and antimuscarinic agents (e.g., atropine).

Inhibits and reverses the vasopressor effect of epinephrine. May antagonise the effects of betahistine and anticholinesterase drugs. May mask the signs of damage caused by ototoxic agents (e.g., aminoglycosides).

Potential fatal: increased risk of cardiac arrhythmia with drugs known to prolong QT interval or induce torsades de pointes.

Benzodiazepine (BZD)

Medication	Main Indications	Initial Daily Dose (mg)	Maintenance Daily Dose Range (mg)	Max Daily Dose (mg)	Relevant Characteristics	Side Effects	Special Precautions	Drug Interactions
ALPRAZOLAM	1. Short-term use for severe acute anxiety in GAD 2. Adjunctive therapy for increased anxiety that may be experienced during initial weeks of treatment with antidepressants	0.25	0.25 - 0.5 BD to TDS / PRN	1.5	Short-acting (about 6 hours)	Dependence and withdrawal symptoms can occur, especially in patients with a history of drug dependence. Central Nervous System effects (e.g., sedation, drowsiness, fatigue, muscle weakness, ataxia, and amnesia. Less commonly, slurred speech, vertigo, headache, confusion) Paradoxical excitement or sleep-related behaviours may occur.	Avoid in patients with a history of drug dependence. Use with Caution in Patients with muscle weakness, respiratory disease, renal or hepatic impairment (avoid if severe) Children, elderly and the debilitated Pregnancy and breastfeeding (avoid use unless potential benefits clearly outweigh risks) History of drug/alcohol abuse or psychiatric disorders (e.g., marked personality disorder, depression, psychosis). Prolonged medication usage (and abrupt discontinuation hereafter) should be avoided Contraindicated in concomitant use with ketoconazole / itraconazole (Strong CYP3A inhibitors), acute narrow angle glaucoma, myasthenia gravis, severe hepatic insufficiency, severe respiratory insufficiency, sleep apnea.	Most BZDs are metabolised by CYP3A4, which is inhibited by erythromycin, several SSRIs and ketoconazole. Coadministration of these drugs may result in higher serum BZD levels. Pharmacodynamic interactions (usually sedation) can occur. BZDs should be used with caution in patients prescribed clozapine (increased risk of cardiopulmonary depression).
CLONAZEPAM		0.25	0.25 - 0.5 BD/ PRN	4	Long-acting (more than 10 hours)
DIAZEPAM		1 - 2	4 - 10 in divided doses (BD/PRN)	10	Long-acting (more than 10 hours)
LORAZEPAM		0.5	0.5 – 2 in divided doses (BD/PRN)	3	Short-acting (about 6 hours)

Table 2. Use of Benzodiazepine (BZDs) for GAD in Primary Care[1,2,12,20-24]

Section 1. General Principles

1. Do not routinely prescribe Benzodiazepines (BZDs) as first-line treatment of GAD because of the potential for dependence and tolerance, which can lead to problems like misuse and addiction, and serious withdrawal symptoms.^26,29

2. GPs should consider the prevailing clinical evidence, local practice guidelines^g, MOH outpatient medical service regulatory guidanceh and MOH administrative guidelines when prescribing BZDsⁱ.

3. Short-term use of BZDs can be considered for severe acute anxiety in GAD.

4. Given the limited evidence on BZDs use as an adjunct for increased anxiety during initial weeks of antidepressant therapy, alternative options should be considered first, e.g. by initiating the antidepressant at low dose, non-pharmacological interventions and/or hydroxyzine. Failing which, short-term BZDs can be considered for distressing symptoms if required.

5. If prescribed, use the lowest effective dose for the shortest duration of time.

6. Aim for short-term use (up to 2 to 4 weeks) and on as-needed dosing.²⁶

7. Educate patients on proper BZD use and review for signs of problems due to dependence or tolerance (Refer to Section 2).²¹

8. Consider specialist assessment if there is inadequate relief from short-term use, or difficulties in reducing or stopping BZD use.

Section 2. Patient communication points on benzodiazepines in GAD²¹

(Source: 2025 GAD ACG – Page 12).

1. Inform the dose, frequency, duration of use, and indication to manage symptoms temporarily.

2. Advise on the adverse effects of the prescribed medication, its potential for tolerance, dependence and addiction. Explain that treatment should be at the lowest effective dose for the shortest duration of time.

3. Inform that BZDs should not be taken with alcohol and other medications that are known to depress the central nervous system (e.g. opioids, hypnotics).

^gMinistry of Health Singapore. MOH Clinical Practice Guidelines – Prescribing of Benzodiazepines. Published: Sep 2008

^h License Conditions for Outpatient Medical Service Licensees: Prescribing and Supplying Benzodiazepines and Other Hypnotics. Imposed under Section 13(1) of the Healthcare Services Act 2020. Effective 26 June 2023.

ⁱMH 70:41/24 Vol. 3 Administrative Guidelines on the Prescribing of Benzodiazepines and Other Hypnotics dated 14 October 2008

Guidelines on Switching Antidepressants^1,21,30,31

General Principles

1. When patients respond poorly to an antidepressant or experience intolerable side effects, GPs should consider switching to another antidepressant

2. The choice of switching strategy is influenced by the following:²¹

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 3)

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 4 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^j can be complex and if uncertain, GPs should consult specialist advice or refer patients to a specialist for management.

^j Monoamine oxidase inhibitors (MAOIs) are not recommended as the 1^st line treatment of GAD due to its potentially serious adverse effect profile, drug-drug and drug-food interactions. MAOIs have a potent hypotensive effect. Use of MAOIs is contraindicated with other antidepressants and medications, such as tramadol and dextromethorphan, due to the risk of serotonin syndrome. MAOIs should be avoided with sympathomimetic agents as its combined use can provoke a hypertensive crisis. MAOIs prevent the breakdown of tyramine, and should not be taken with tyramine-rich containing food (e.g., aged cheeses, meat, fish and poultry) as this can trigger a hypertensive crisis (tyramine pressor response).^27,28

Table 3. 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 4. Specific Switching Between Antidepressants[k]

^kThe 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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