Previous changes

February 2025 — minor update. Added detail relating to the NICE guidance Gambling-related harms: identification, assessment and management.

December 2024 — minor update. Added information about monitoring people treated with pregabalin for signs and symptoms of pregabalin misuse, abuse, or dependence, in line with the updated manufacturer's SPC.

July 2024 — minor update. Adverse effects of neuroleptic malignant syndrome (NMS) and stress cardiomyopathy relating to Deuloxetine has been added in line with an update to the manufacturer’s SPC. 

February 2024 — minor update. An adverse effect of hyperprolactinaemia relating to Citalopram has been added in line with an update to the manufacturer’s SPC. Interaction between pregabalin and morphine sulfate has been added in line with an update to the manufacturer’s SPC. Added information about prescribing diazepam to people who are breastfeeding with caution.

December 2023 — minor update. An adverse effect of leukopenia relating to paroxetine has been added in line with an update to the manufacturer's SPC.

February 2023 — minor update. Added detail about prescribing paroxetine with caution in people with a (family) history of QT prolongation, concomitant use of anti-arrhythmics or other drugs prolonging QT interval, relevant pre-existing cardiac disease, and hypokalaemia or hypomagnesemia in line with an update to the manufacturer's SPC. 

June 2022 — reviewed. A literature search was conducted in May 2022 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. Some minor structural changes have been made to this topic, but there have been no major changes to the recommendations.

March 2022 — minor update. Contraindication to pregabalin use in pregnancy unless the benefits to the mother outweigh the risks to the foetus in line with the manufacturer's summary of product characteristics. 

February 2022 — minor update. Parkinsonism added as an adverse effect of pregabalin in line with updated manufacturer's SPC.

February 2021 — minor update. Sertraline drug interactions updated in line with revised manufacturer's SPC.

December 2020 — minor update. Severe respiratory depression added as an adverse effect of pregabalin in line with updated manufacturer's SPC.

July 2020 — minor update. Venlafaxine cardiac adverse effects updated in line with revised manufacturer's SPC. 

March 2020 — minor update. Takotsubo cardiomyopathy has been added as an adverse effect of venlafaxine modified release in line with updated manufacturer's SPC.

August to October 2017 —  reviewed. A literature search was conducted in August 2017 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. The topic has undergone restructuring. No major changes to the recommendations have been made.

July 2017 — minor update. Addition to adverse effects for pregabalin to reflect changes to the manufacturer's Summary of Product Characteristics.

October 2015 — minor update. Based on an update to the manufacturer's Summary of Product Characteristics (SPC):

• Gynaecological haemorrhage and severe and potentially fatal allergic reactions (very rare) have been included as possible adverse effects of paroxetine.
• The drug interaction section has been updated to include the possible interaction between selective serotonin reuptake inhibitors (SSRIs) and pravastatin.

April 2015 — minor update. Update to the text to reflect a new law on drugs and impaired driving.

July 2013 — minor update. Links to the DVLA website have been updated.

January to June 2013 — this is a new CKS topic. The evidence base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

New evidence

Evidence-based guidelines

• NICE (2025) Gambling-related harms: identification, assessment and management National Institute for Health and Care Excellence Homepage | NICE [Free full-text]

HTAs (Health Technology Assessments)

• NICE (2023) Digitally enabled therapies for adults with anxiety disorders: early value assessment. www.nice.org.uk [Free Full-text]

Economic appraisals

No new economic appraisals relevant to England since 1 June 2022.

Systematic reviews and meta-analyses

No new systematic reviews or meta-analysis which reach the CKS threshold for inclusion since 1 June 2022.

Primary evidence

• Bazo-Alvarez, J.C., Nimmons, D., Walters, K., et al. (2024) Risk of Parkinson's disease in people with New Onset Anxiety over 50 years - Incidence and Associated Features. British Journal of General Practice. https://bjgp.org/ [Abstract]

New policies

No new national policies or guidelines since 1 June 2022.

New safety alerts

No new safety alerts since 1 June 2022.

Changes in product availability

• New Product Enalto (escitalopram) orodispersible tablets. This new formulation, available in 5, 10, 15 and 20mg strengths, is licensed for the treatment of generalised anxiety disorder. See more here.

Basis for recommendation

These recommendations are based on the World Health Organization (WHO) International Statistical Classification of Diseases and Related Health Problems, 11th Revision (ICD-11) [WHO, 2022], the American Psychiatric Association (APA) Diagnostic and Statistical Manual of Mental Disorders DSM-5-TR [APA, 2022], the BMJ Best Practice guide Generalised anxiety disorder [BMJ, 2021], the National Institute for Health and Care Excellence (NICE) guidelines Generalized anxiety disorder and panic disorder in adults: management [NICE, 2020a] Common mental health problems: identification and pathways to care [NICE, 2022], and Gambling-related harms: identification, assessment and management [NICE, 2025], the Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of panic disorder, social anxiety disorder and generalised anxiety disorder [Andrews, 2018], and the British Association for Psychopharmacology guideline Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology [Baldwin, 2014].

DSM-5-TR and ICD-11 criteria

• While the DSM-5-TR and ICD-11 criteria broadly overlap, they differ in terms of some details, including duration of symptoms. Clinical judgement should therefore be used to determine the overall likelihood of a diagnosis of GAD. 

Use of GAD questionnaires

• NICE recommends the use of the GAD-2 or GAD-7 as part of the assessment for GAD [NICE, 2022].
  • The GAD-2 is a shortened version of GAD-7 consisting of the first two questions. An example of the GAD-7 questionnaire can be found within the NICE full guideline [NICE, 2021]. 

Assess the risk of suicide

• The recommendation to assess the risk of suicide is based on an Australian and New Zealand guideline which recommends that all people with anxiety disorders should be assessed for suicidal thinking and the risk of self-harm [Andrews, 2018], the NICE guideline which recommends that people with a risk of self-harm or suicide should be referred for specialist assessment [NICE, 2020a], and a German guideline which recommends that amongst other things, treatment decisions should take into account suicide risk [Bandelow, 2022].    

How should I manage a person with generalized anxiety disorder?

The National Institute for Health and Care Excellence (NICE) recommends a stepped approach in the management of generalized anxiety disorder (GAD).

• Step 1 — for all people with GAD:
  • Communicate the diagnosis of GAD as early as possible to help people understand the disorder and start effective treatment promptly. 
  • Provide information about the nature of GAD and treatment options. For example, the NICE document Treating generalised anxiety disorder and panic disorder in adults and the NHS website information on Generalised anxiety disorder in adults.
  • Arrange active monitoring of the person's symptoms and functioning at intervals based on clinical judgement.  
  • And a comorbid depressive or other anxiety disorder, treat the primary disorder first (that is, the one that is more severe and in which it is more likely that treatment will improve overall functioning). Also ensure that other comorbid conditions are optimally managed. 
• Step 2 — for people with GAD whose symptoms have not improved, offer one of the following low-intensity psychological interventions, guided by the person's preference: 
  • Individual non-facilitated self-help — based on cognitive behavioural therapy (CBT) principles, this should include suitable written or electronic materials that the person works through systematically over a period of at least 6 weeks. It usually involves minimal therapist contact, for example an occasional short telephone call of no more than 5 minutes, if required.
  • Individual guided self-help — should include suitable written or electronic materials, and be supported by a trained practitioner who facilitates the programme and reviews progress and outcomes. This usually consists of 5–7 weekly or fortnightly face-to-face or telephone sessions, each lasting 20–30 minutes.
  • Psychoeducational groups — based on CBT principles, this should have an interactive design and encourage observational learning through presentations and self-help manuals. Conducted by trained practitioners, there should be a ratio of one therapist to 12 participants and usually consist of 6 weekly 2-hour sessions. 
• Step 3 — for people with GAD and marked functional impairment, or with GAD that has not improved following step 2 interventions, offer one of the following guided by the person's preference:
  • An individual high-intensity psychological intervention such as CBT or applied relaxation.
    • These usually consist of 12–15 weekly sessions each lasting 1 hour.
    • Inform the person that the response to psychological treatment is not immediate and that a prolonged course is usually needed to maintain an initial response.
  • Drug treatment — offer a selective serotonin reuptake inhibitor (SSRI) first line. 
    • If sertraline is ineffective, offer an alternative SSRI, for example, paroxetine or escitalopram, or a selective serotonin-noradrenaline reuptake inhibitor (SNRI), such as duloxetine or venlafaxine. 
    • If the person cannot tolerate SSRIs or SNRIs, consider offering pregabalin. For more information, see the relevant sections in Prescribing information. 
    • Before prescribing any medication, discuss the treatment options, any concerns the person may have, explain the reason for prescribing and provide written and verbal information on the likely benefits, potential for adverse effects, and withdrawal symptoms.
    • Explain that adverse effects early in treatment with an SSRI or SNRI may include increased anxiety, agitation, and sleeping problems, and that there will be a gradual improvement in symptoms over 1 week or more before they experience the full anxiolytic effect. 
    • Review the effectiveness and adverse effects of the drug every 2–4 weeks during the first 3 months of treatment and every 3 months thereafter. Dose adjustment may be required. Modest benefit is usually seen within 6 weeks and continues to increase over time.
    • Advise people aged under 30 years that in a minority of people aged under 30 years, SSRIs and SNRIs are associated with an increased risk of suicidal thinking and self-harm. Anyone in this age group receiving an SSRI or SNRI should therefore be seen within 1 week of first prescribing, and the risk of suicidal thinking and self-harm should be monitored weekly for the first month. 
    • Do not offer a benzodiazepine for the treatment of GAD in primary care, except as a short-term measure during crises. For more information, see the section on Prescribing information. 
    • Do not offer an antipsychotic for the treatment of GAD in primary care.
• If a pregnant woman with GAD requires step 3 management:
  • Ideally, offer a high-intensity psychological intervention first-line.
  • A decision on starting drug treatment should take into account the benefits and harms of treatment in pregnancy, including the risk of not treating the condition, and the risks or harms to the woman and fetus (or baby) associated with the treatment.
    • This should be discussed with the woman.
    • Data on the risk of congenital malformations (including heart defects) following use of SSRIs or SNRIs in early pregnancy are conflicting and confounded, so the teratogenic potential is unproven. The available data for pregabalin do not currently indicate that maternal pregabalin use in pregnancy is associated with an increased risk of malformations, or miscarriage, or adversely affects fetal growth. 
  • If a woman becomes pregnant while on medication for GAD, discuss the option of stopping the medication and gradually switching to a psychological intervention. Take into account the risk of relapse when considering discontinuing or switching medication.
    • In cases where drug treatment is continued in pregnancy, the lowest effective dose should be used.
  • Treatment with an SSRI or SNRI after around 20 weeks of pregnancy may increase the risk of persistent pulmonary hypertension of the newborn (PPHN) and/or can lead to neonatal withdrawal.
    • Women using these medications should be informed of the potential increased risk of PPHN. 
  • Seek specialist advice, preferably from a specialist in perinatal mental health, if there is any uncertainty about drug treatment (for example if starting medication, or if changes need to be made to SSRI or SNRI medication in pregnancy). 
    • Patient information leaflets on use of drugs to treat GAD in pregnancy are available at medicinesinpregnancy.org.
• Step 4 — for people with complex, treatment-refractory GAD and very marked functional impairment, or high risk of self-harm:
  • Offer referral for specialist assessment of needs and risks. 
  • Inform people with GAD who have not been offered or have refused the interventions in steps 1–3 about the potential benefits of these interventions and offer any they have not tried. 
  • Advise carers about their right to carer assessment, and assessment for respite care and other support. 
• For all people with GAD managed in primary care, also consider providing self-care about:
  • Sleep hygiene — such as going to bed and waking up at the same time each day, eliminating alcohol after 6 pm, avoiding caffeine after 3 pm, and getting out of bed if unable to fall asleep to avoid negative associations with the sleep environment. For more information, see the CKS topic on Insomnia.
  • The benefits of regular exercise — this can improve overall health and has been shown to improve anxiety symptoms.
  • Over-the-counter medicines and preparations — explain the potential for interactions with other prescribed and over-the-counter medications and the lack of evidence to support their safe use.

General information

• The SSRIs most commonly prescribed in the UK for the treatment of generalized anxiety disorder (GAD) are:
  • Sertraline.
  • Paroxetine.
  • Escitalopram.
• There is no evidence that any one is more effective than the others in the treatment of GAD. 
• Escitalopram and paroxetine are licensed in the UK for the treatment of GAD, whilst the others are not. 
• Sertraline is often used first-line as it is the most cost-effective, but as it is not licensed for the treatment of GAD, informed consent should be obtained and documented. 
• Other known clinical advantages of sertraline include its minimal drug interactions (making it preferable to paroxetine), a lack of associated electrocardiographic changes (compared with escitalopram), and its lower risk of symptoms on discontinuation (compared with paroxetine). 
• Choice of SSRI should also take into account the person's preference, and their prior experience of treatment with individual drugs (particularly adherence, effectiveness, adverse effects, and experience of withdrawal syndrome). 
• Treatment should be continued for at least 1 year. 
  •  Modest benefit is usually seen within 6 weeks and continues to increase over time.

 [Hoge, 2012; NICE, 2020a; ABPI, 2021a; ABPI, 2022a; ABPI, 2022b; Taylor, 2021; BNF, 2022]

Contraindications and cautions

• Do not prescribe SSRIs to people:
  • In a manic phase of bipolar disorder. 
  • Taking monoamine oxidase inhibitors (MAOIs), or who have recently discontinued an MAOI. 
  • Taking pimozide. 
  • With poorly controlled uncontrolled epilepsy or new onset seizures.
• Do not prescribe escitalopram to people with:
  • Known QT interval prolongation, or susceptibility to QT interval prolongation (for example, taking medicines that are known to prolong the QT interval), or congenital long QT syndrome. 
• Prescribe SSRIs with caution to people with:
  • A history of bleeding disorders, especially gastrointestinal bleeding. 
    • Older people or people taking drugs that can damage the gastrointestinal mucosa or interfere with clotting (for example, nonsteroidal anti-inflammatory drugs or aspirin) may also be at risk. Consider prescribing a gastroprotective drug in these circumstances.
  • People with a (family) history of QT prolongation, concomitant use of anti-arrhythmics or other drugs prolonging QT interval, relevant pre-existing cardiac disease, and hypokalaemia or hypomagnesemia.
  • Diabetes mellitus. 
  • Epilepsy (discontinue if convulsions develop). 
  • History of mania.
  • Susceptibility to angle-closure glaucoma.
• Also prescribe SSRIs with caution to people:
  • Undergoing concurrent electroconvulsive therapy. 
• In addition, prescribe escitalopram with caution to people at higher risk of developing Torsade de Pointes. This includes people with:
  • Congestive heart failure. 
  • Recent myocardial infarction. 
  • Significant bradycardia.  
  • Concomitant illness or medication causing a predisposition to hypokalaemia or hypomagnesaemia. 

[ABPI, 2021a; ABPI, 2022a; ABPI, 2022b; BNF, 2022]

What adverse effects are associated with SSRIs?

• The most common adverse effects associated with SSRIs include:
  • Central nervous system — including dizziness, headache, and tremor.
  • Gastrointestinal — these are dose-related and include nausea, vomiting, abdominal pain, dyspepsia, constipation, and diarrhoea. 
  • Psychiatric — insomnia, agitation, anxiety, depression. 
• Other common adverse effects include: 
  • Hot flush.
  • Palpitations.
  • Sexual dysfunction — this is also a common symptom of generalized anxiety disorder. 
  • Visual disturbance.
  • Yawning.
• Other adverse effects include:
  • Hyponatraemia — may be due to inappropriate antidiuretic hormone secretion (SIADH). Usually resolves on discontinuation of therapy. People at greater risk include the elderly, people taking diuretics or who are otherwise volume-depleted.
    • Signs and symptoms of hyponatraemia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
  • Increased risk of bleeding, especially in older people or people taking other drugs that can damage the gastrointestinal mucosa or interfere with clotting (for example nonsteroidal anti-inflammatory drugs [NSAIDs]). The risk of postpartum haemorrhage may be increased. 
  • Leukopenia — has been reported as an uncommon adverse drug reaction in people prescribed paroxetine.
  • Increased risk of fractures — the Medicines and Healthcare products Regulatory Agency (MHRA) has advised that SSRIs are associated with a small increased risk of fractures; however, the mechanism leading to this is unclear and may be multifactorial. 
  • Increased suicide risk — this is most likely in younger people (aged up to 25 years) when starting an SSRI. 
    • Monitor people carefully during the first few weeks of SSRI treatment; in particular, be alert for clinical worsening, suicidal behaviour or thoughts, and unusual changes in behaviour. 
  • Discontinuation symptoms (such as dizziness, sensory disturbances [including paraesthesia], sleep disturbances [including insomnia and intense dreams], agitation or anxiety, nausea and/or vomiting, tremor, and headache). 
    • The risk of discontinuation symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. 
    • Generally, these symptoms are mild to moderate and self-limiting and usually resolve within 2 weeks. However, in some people, they may be severe or prolonged (2–3 months or more).
    • They usually occur within the first few days of discontinuing treatment. 
    • SSRIs should be gradually tapered over a period of several weeks or months, according to the person's needs. 
    • Paroxetine is associated with a higher incidence of discontinuation symptoms than other selective serotonin reuptake inhibitors. 
  • For escitalopram, QT prolongation and/or ventricular arrhythmias; especially in women, people with hypokalaemia, or people with pre-existing QT interval prolongation or another cardiac disease.

[MHRA, 2014; ABPI, 2021a; ABPI, 2022a; ABPI, 2022b; BNF, 2023; EMC, 2023]

What are the key drug interactions with SSRIs?

Key drug interactions for SSRIs include:

• Anticonvulsants — SSRIs antagonize anticonvulsant effect of antiepileptics (convulsive threshold lowered).
• Antiplatelets (for example, clopidogrel) — bleeding risk may be increased. Advise patients to report bleeding. Consider gastroprotection (such as a proton pump inhibitor) in those at high risk of gastrointestinal bleeding.
• Coumarin anticoagulants — SSRIs possibly enhance anticoagulant effect of coumarins.
  • Consider frequent monitoring of international normalized ratio (INR). Any change in the person's clinical condition, particularly liver disease, intercurrent illness, or drug administration, necessitates more frequent monitoring of the INR. 
• Cyproheptadine — antidepressant effect of SSRIs possibly antagonized by cyproheptadine.
• Direct oral anticoagulants (for example, dabigatran) — increased risk of bleeding. Monitor for signs of bleeding or anaemia, and discontinue if severe bleeding occurs.
• Methylphenidate — metabolism of SSRIs possibly inhibited.
• Nonsteroidal anti-inflammatory drugs (for example, naproxen) — increased risk of bleeding. Advise about possible risks and consider giving an alternative analgesic. 
• Pimozide — SSRIs possibly increase plasma concentration of pimozide. Increased risk of ventricular arrhythmias — avoid concomitant use.
• Ritonavir — plasma concentration of SSRIs possibly increased.
• Serotonergic medicines — concurrent use of SSRIs with other serotonergic medicines increases the risk of serotonin syndrome or neuroleptic malignant syndrome.
  • St John's wort — avoid concurrent use.
  • Lithium — be alert for symptoms of neurotoxicity (such as tremor, dysarthria, ataxia, confusion) and serotonin syndrome (such as weakness, hyperreflexia, incoordination).
  • Triptans (for example, naratriptan) — if concurrent use is necessary, monitor closely for signs of serotonin syndrome. 
  • Fentanyl, tramadol —  if concurrent use is necessary, monitor closely for signs of serotonin syndrome. 
  • Monoamine oxidase inhibitors (MAOIs) — serious and potentially life-threatening reactions can develop if an SSRI and non-selective, irreversible MAOIs are given concurrently, or even sequentially if insufficient time is left in between. The manufacturers recommend that 1 week should elapse between stopping SSRI and starting an MAOI, and that 2 weeks should elapse between stopping an MAOI and starting an SSRI. 
    • Concurrent use with reversible MAOIs is also contraindicated due to the risk of serotonin syndrome. 
• Tricyclic antidepressants (for example, amitriptyline) — SSRIs increase plasma concentration of some tricyclics.

Key drug interactions for escitalopram include:

• Drugs that prolong the QT interval — do not prescribe concurrently with drugs that prolong the QT interval, including some antiarrhythmics (for example, amiodarone), antipsychotics (such as haloperidol), antihistamines (such as mizolastine), and antiretrovirals (such as ritonavir, saquinavir, and lopinavir). 
• Serotonergic medicines — co-administration of these medication such opioids (including tramadol), and triptans (including sumatriptan) may lead to serotonin syndrome; caution is therefore advised if escitalopram is used concomitantly with these medicines.

Key drug interactions for paroxetine include: 

• Aripiprazole — concentrations may be increased. Monitor for adverse effects.
• Clozapine — small to modest increases in clozapine concentrations may occur. Increase monitoring of clozapine concentrations, adjusting the clozapine dose as necessary.
• Methadone — concentrations of methadone may be increased. Be alert for an increase in adverse effects particularly with high doses of methadone.
• Metoprolol — metoprolol levels increased. Manufacturer advises avoiding concurrent use if metoprolol is used for heart failure.  If concurrent use is necessary, monitor for hypotension and bradycardia.
• Risperidone — risperidone concentrations are increased, and concurrent use may increase the risk of QT interval prolongation. Monitor for risperidone adverse effects and reduce the dose as needed. Consider monitoring ECG in people with risk factors for QT interval prolongation.
• Tamoxifen — paroxetine reduces tamoxifen metabolism to one of the active metabolites, potentially increasing the risk of breast cancer recurrence. Avoid concurrent use. 
• Thioridazine — levels of thioridazine may be increased, potentially increasing the risk of QT interval prolongation. Consider monitoring ECG in people with other risk factors. Manufacturers advise that concurrent use is contraindicated. 

[ABPI, 2021a; ABPI, 2022a; ABPI, 2022b; BNF, 2022; Preston, 2023]

What dose of escitalopram, paroxetine, or sertraline should I use and how should I titrate the dose?

• For sertraline: prescribe a starting dose of 25 mg daily, then increase to 50 mg daily after 1 week. If required, increase in steps of 50 mg at intervals of at least 1 week to a maximum of 200 mg a day.
  • Be aware that sertraline is not licensed for use in generalized anxiety disorder (GAD). The recommended doses are licensed doses for social anxiety disorder and panic disorder. 
• For escitalopram: prescribe a starting dose of 10 mg daily. Increase dose gradually according to response up to a maximum of 20 mg a day (except in elderly people and those with reduced hepatic function). 
• For paroxetine: prescribe a starting dose of 20 mg daily. The maximum licensed dose for the treatment of GAD is 50 mg/day. 
  • There is no evidence of greater efficacy at doses over 20 mg. 
• If changing between anxiolytic medications:
  • When switching from one SSRI to another, cross tapering is not necessary, as the new drug will generally ameliorate withdrawal symptoms from the old one. 
  • When switching from an SSRI to an SNRI, or from an SNRI to an SSRI a direct switch is possible. 
    • If switching from an SSRI to duloxetine, start from 60 mg daily.
  • For information on switching to and from other groups of antidepressants, see the section on switching antidepressants in the CKS topic on Depression.

[Taylor, 2021; BNF, 2022]  

General information

• The SNRIs duloxetine and venlafaxine modified-release are both licensed in the UK for the treatment of generalized anxiety disorder (GAD). 
• Both have been shown to be effective in the treatment of GAD. 
• Choice of SNRI should also take into account the person's preference, and their prior experience of treatment with individual drugs (particularly adherence, effectiveness, adverse effects, and experience of withdrawal syndrome). 
• Treatment should be continued for at least 1 year. 
  •  Modest benefit is usually seen within 6 weeks and continues to increase over time.

[NICE, 2020a; ABPI, 2021b; Taylor, 2021; ABPI, 2022c]

Contraindications and cautions of duloxetine and venlafaxine modified-release

• Do not prescribe SNRIs to people:
  • With uncontrolled hypertension. 
  • Taking a monoamine oxidase inhibitor (MAOI), or who have recently discontinued an MAOI. 
• Do not prescribe duloxetine to people with:
  • Hepatic impairment. 
  • Severe renal impairment (creatinine clearance less than 30 mL/min).
• Prescribe an SNRI with caution to people with:
  • A history of mania. 
  • A history of seizures. 
  • Bleeding disorders. 
    • Older people or people taking drugs that can damage the gastrointestinal mucosa or interfere with clotting (for example, nonsteroidal anti-inflammatory drugs or aspirin) may also be at risk. Consider prescribing a gastroprotective drug in these circumstances.
  • Cardiac disease. 
  • Hypertension.
    • For duloxetine, blood pressure monitoring is recommended, especially during the first month of treatment. For people who experience a sustained increase in blood pressure while receiving duloxetine, either dose reduction or gradual discontinuation should be considered. 
    • For venlafaxine, all people should therefore be screened for high blood pressure and pre-existing hypertension should be controlled before initiation of treatment. Blood pressure should be reviewed periodically, after initiation of treatment, and after dose increases. 
    • With use of duloxetine or venlafaxine, caution should be exercised in people whose underlying conditions might be compromised by increases in blood pressure, such as those with impaired cardiac function. 
  • Susceptibility to angle-closure glaucoma or increased intraocular pressure.
• Prescribe duloxetine with caution to:
  • Older people. 
  • People taking other medicinal products associated with hepatic injury. 
• Prescribe venlafaxine with caution to people with:
  • A recent history of myocardial infarction. 
  • Conditions associated with high risk of cardiac arrhythmia.
  • Diabetes mellitus. 

[ABPI, 2021b; ABPI, 2022c; BNF, 2022]

What adverse effects are associated with duloxetine and venlafaxine modified-release?

• The most common adverse effects associated with SNRIs include:
  • Central nervous system — headache, somnolence, dizziness, lethargy, tremor, paraesthesia.
  • Gastrointestinal — nausea, dry mouth, constipation, diarrhoea, abdominal pain, vomiting, dyspepsia, flatulence.
  • Psychiatric — insomnia, agitation, anxiety, abnormal dreams. 
• Other common adverse effects include:
  • Blurred vision.
  • Flushing.
  • Palpitations.
  • Sexual dysfunction — this is also a common symptom of generalized anxiety disorder.  There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SNRIs. 
  • Tinnitus.
  • Yawning.
• Other adverse effects of duloxetine and venlafaxine include:
  • Hypertension. 
    • Venlafaxine is commonly associated with dose-related increases in blood pressure. Severely elevated blood pressure requiring immediate treatment has been reported in post-marketing experience. 
    • Duloxetine has been associated with increased blood pressure, and clinically significant hypertension in some people. Cases of hypertensive crisis have been reported, especially in people with pre-existing hypertension. 
  • Hyponatraemia — may be due to inappropriate antidiuretic hormone secretion (SIADH). Usually resolves on discontinuation of therapy. People at greater risk include the elderly, people taking diuretics or who are otherwise volume-depleted. 
  • Increased risk of bleeding, especially in older people or people taking other drugs that can damage the gastrointestinal mucosa or interfere with clotting (for example nonsteroidal anti-inflammatory drugs [NSAIDs]). The risk of postpartum haemorrhage may be increased. 
  • Increased suicide risk — this is most likely in younger people (aged up to 25 years) when starting an SNRI.
    • Monitor people carefully during the first few weeks of SNRI treatment; in particular, be alert for clinical worsening, suicidal behaviour or thoughts, and unusual changes in behaviour. 
  • Discontinuation symptoms (such as dizziness, sensory disturbances [including paraesthesia], sleep disturbances [including insomnia and intense dreams], agitation or anxiety, nausea and/or vomiting, tremor, and headache).
    • The risk of discontinuation symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. 
    • Generally, these symptoms are mild to moderate and self-limiting and usually resolve within 2 weeks. However, in some people, they may be severe, or prolonged (2–3 months or more).
    • They usually occur within the first few days of discontinuing treatment.
    • It is therefore advised that an SNRI should be gradually tapered over a period of no less than 2 weeks, according to the person's needs. 
• Other adverse effects of venlafaxine include:
  • • Altered glycaemic control in people with diabetes mellitus. Monitor diabetic control and adjust oral anti-diabetic or insulin doses if necessary. 
    • Fatal cardiac arrhythmias have been reported, especially in overdose. The balance of risks and benefits should therefore be considered before prescribing venlafaxine to people at high risk of serious cardiac arrhythmia. 
    • Takotsubo or stress cardiomyopathy. 
• Other adverse effects of duloxetine include:
  • Liver injury — including severe elevations of liver enzymes (>10 times upper limit of normal), hepatitis, and jaundice. This is most likely during the first months of treatment.
  • Neuroleptic malignant syndrome (NMS) may occur with duloxetine treatment, and that in its most severe form, serotonin syndrome can resemble NMS.
  • Stress cardiomyopathy (Takotsubo cardiomyopathy).
• Other adverse effects of citalopram include:
  
  • Hyperprolactinaemia, which is an effect of unknown frequency.

[ABPI, 2021b; ABPI, 2022c; BNF, 2022]  [EMC, 2024a; EMC, 2024b]

What key drug interactions with duloxetine or venlafaxine modified-release should I be aware of?

Key drug interactions with SNRIs as a class include:

• Anticoagulants and antiplatelets — bleeding risk may be increased. 
• Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) — increased risk of bleeding.
• Monoamine oxidase inhibitors (MAOIs) — serious and potentially life-threatening reactions can develop if an SNRI and non-selective, irreversible MAOIs are given concurrently. Avoid concurrent use. SNRIs should not be started until at least 2 weeks after stopping an MAOI, and an SNRI should be stopped 5 days before starting an MAOI (2 weeks for selegiline).  
• Serotonergic medicines — concurrent use of sertraline with other serotonergic medicines increases the risk of serotonin syndrome or neuroleptic malignant syndrome. If concurrent use is necessary, monitor for symptoms of serotonin syndrome (such as fever, tremors, diarrhoea, agitation).
  • St John's wort.
  • Lithium.
  • Triptans (for example, naratriptan).
  • Fentanyl, tramadol.
  • SSRIs.

Interactions for duloxetine also include:

• Tricyclic antidepressants (for example, amitriptyline, clomipramine) — concentrations are increased by duloxetine, and there is a theoretical risk of serotonin syndrome. Monitor for increased tricyclic adverse effects. 
• Ciprofloxacin — metabolism of duloxetine is inhibited by ciprofloxacin. If both drugs are necessary, monitor for duloxetine adverse effects (nausea, headache, insomnia).

Interactions for venlafaxine also include: 

• Drugs associated with QT interval prolongation, for example:
  • Amiodarone — dangerous QT prolongation might occur if used concurrently. If concurrent use is unavoidable consider ECG monitoring.
  • Domperidone — concurrent use is contraindicated.
  • Disopyramide — dangerous QT prolongation might occur if used concurrently. If concurrent use is unavoidable consider ECG monitoring.
  • Erythromycin — levels of venlafaxine may be increased, and both drugs have been associated with QT interval prolongation. Be aware of the potential for an interaction and adjust the dose of venlafaxine should adverse effects occur.
  • Mizolastine — concurrent use is contraindicated.
  • Moxifloxacin — consider ECG monitoring in people at increased risk of QT interval prolongation (for example, older age, female sex, cardiac disease, metabolic disturbances). 
  • Sotalol — dangerous QT prolongation might occur if used concurrently, and blood pressure-lowering effects might also be reduced. If concurrent use is unavoidable consider ECG monitoring and monitor blood pressure.
• Antifungals (for example, fluconazole, posaconazole, voriconazole) — levels of venlafaxine may be increased. Be aware of the potential for an interaction and adjust the dose of venlafaxine should adverse effects occur.
• Bupropion — plasma concentration of venlafaxine increased by bupropion. Be alert for any indication of increased venlafaxine adverse effects.
• Haloperidol — venlafaxine increases plasma concentration of haloperidol. Dangerous QT prolongation may occur. If concurrent use is unavoidable consider ECG monitoring.
• HIV protease inhibitors (for example, ritonavir)— increased levels of venlafaxine. Monitor for venlafaxine adverse effects (nausea, insomnia, dry mouth), and adjust the dose if necessary.

[ABPI, 2021b; ABPI, 2022c; BNF, 2022; Preston, 2023]

What dose of duloxetine or venlafaxine modified-release should I use and how should I titrate the dose?

• For duloxetine: prescribe a starting dose of 30 mg daily. Increase to 60 mg daily if necessary; the maximum licensed dose for generalized anxiety disorder is 120 mg daily. 
• For venlafaxine modified-release: prescribe a starting dose of 75 mg daily. Increase gradually if necessary at intervals of 2 weeks up to a maximum dose of 225 mg daily. 
• If changing between anxiolytic medications:
  • When switching from duloxetine to venlafaxine a direct switch is possible. 
  • When switching from an SSRI or venlafaxine to duloxetine a direct switch is possible, starting from 60 mg daily. 
  • When switching from an SNRI to an SSRI a direct switch is possible.
  • For information on switching to and from other groups of antidepressants, see the section on switching antidepressants in the CKS topic on Depression.

[Taylor, 2021; BNF, 2022] 

Contraindications and cautions of pregabalin

• Pregabalin should not be used in women who are pregnant, unless the benefit to the mother clearly outweighs the potential risk to the fetus.
• People treated with pregabalin should be monitored for signs and symptoms of pregabalin misuse, abuse or dependence, such as development of tolerance, dose escalation and drug-seeking behaviour.
• Prescribe pregabalin with caution to people with:
  • A history of substance abuse. 
    • Evaluate people carefully for a history of drug abuse before prescribing pregabalin and observe for signs of abuse and dependence. 
  • Conditions that may precipitate encephalopathy. 
  • Diabetes mellitus — pregabalin may cause weight gain. People with diabetes who gain weight on pregabalin may need to adjust their anti-diabetic medication.
  • Renal impairment — dose adjustments may be necessary. For more information, see the section on dose and titration. 
  • Respiratory depression — consider whether adjustments in dose or dosing regimen are necessary in people at higher risk of respiratory depression, including those: 
    • With compromised respiratory function, respiratory or neurological disease, or renal impairment.
    • Taking other central nervous system depressants (including opioid-containing medicines).
    • Aged older than 65 years.
  • Severe congestive heart failure. 
• Also prescribe pregabalin with caution to people who are:
  • Elderly. 
  • At risk of falls — pregabalin has been associated with dizziness and somnolence, and there have been post-marketing reports of loss of consciousness, confusion, and mental impairment.
  • At risk of suicide — there is a small increased risk of suicidal ideation and behaviour in people treated with antiepileptic drugs. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for pregabalin.
    • Monitor at-risk people for signs of suicidal ideation. 
  • Using medications that can cause constipation (such as opioids) — there are post-marketing reports of events related to reduced lower gastrointestinal tract function (such as intestinal obstruction, paralytic ileus, and constipation) when pregabalin was co-administered with such medications. 
    • During combination therapy, measures to prevent constipation should be considered, especially in women and older people.

[MHRA, 2019; ABPI, 2022d; BNF, 2022; EMC, 2024c]

What are the adverse effects of pregabalin?

Common adverse effects of pregabalin include:

• Central nervous system — dizziness, somnolence, headache, abnormal coordination, tremor, dysarthria, amnesia, memory impairment, inattention, paraesthesia, hypoaesthesia, sedation, balance disorder, lethargy. 
• Eye — blurred vision and diplopia.
• Gastrointestinal — vomiting, nausea, constipation, diarrhoea, flatulence, abdominal distension, dry mouth.
• Musculoskeletal and connective tissue — muscle cramp, arthralgia, back pain, limb pain, cervical spasm.
• Psychiatric — euphoria, confusion, irritability, decreased libido, disorientation, insomnia. 
  • Suicidal thoughts and behaviour — there is a small increased risk of suicidal thoughts and behaviour associated with antiepileptic drugs (including pregabalin), which may be seen as early as 1 week after starting treatment. 
  • People should seek medical advice if they develop such thoughts or behaviour, and they should be referred for appropriate treatment if necessary.
  • Advise people taking pregabalin to be alert to any mood changes, distressing thoughts, or feelings about suicide or harming themselves at any point during treatment.

Other adverse effects include:

• Erectile dysfunction.
• Increased appetite and weight gain. 
• Nasopharyngitis.
• Parkinsonism.
• Severe respiratory depression — advise people to seek medical help if they experience any trouble breathing or shallow breathing; a noticeable change in breathing may be associated with sleepiness. 
• Vertigo.

[ABPI, 2022d; BNF, 2022]

What are the key drug interactions with pregabalin?

• Central nervous system (CNS) depressants (such as alcohol, benzodiazepines, opioids) — there may be additive sedative effects if pregabalin is used with other CNS depressants. 
  • Respiratory failure, coma, and death have been reported in people taking pregabalin and opioids and/or other CNS depressants. 
  • Advise people taking pregabalin of the potentially fatal risks of interactions between pregabalin and alcohol, and with other medicines that cause CNS depression, particularly opioids.
• Clozapine — levels may be increased if taken concurrently with pregabalin. Monitor for clozapine adverse effects (for example, agitation, dizziness, sedation, hypersalivation).
• Drugs known to cause constipation (for example, opioid analgesics) — reduced lower gastrointestinal tract function may occur, potentially leading to intestinal obstruction, paralytic ileus, and/or constipation.
• Lacosamide — prolongation of the PR interval may occur with lacosamide, it should be used with caution in people taking pregabalin, which may also cause PR prolongation.
• Orlistat — the levels of pregabalin may be reduced. 
• Morphine — interaction of pregabalin and morphine increases risk of respiratory depression.

[MHRA, 2019; ABPI, 2022d; Preston, 2023; EMC, 2024d]

What dose of pregabalin should I prescribe and how should I titrate the dose?

• Prescribe a starting dose of 150 mg daily (in two to three divided doses). If required, increase in steps of 150 mg daily at 7-day intervals. Maximum dose 600 mg daily in two to three divided doses. 
• A lower starting dose may be appropriate for people with reduced renal function. Please see Table 2 for further details. 
• Seek specialist advice and consult the manufacturer's Summary of Product Characteristics for people undergoing haemodialysis.

Table 2. Recommended dosages of pregabalin based on renal function. 

[ABPI, 2022d; BNF, 2022]

Contraindications and cautions of diazepam

• Do not prescribe diazepam to people with:
  • Acute porphyria. 
  • Acute pulmonary insufficiency, compromised airways, respiratory depression. 
  • Chronic psychosis (as monotherapy), phobic or obsessional states, hyperkinesis, depression or anxiety associated with depression (as monotherapy). 
  • Central nervous system depression. 
  • Marked neuromuscular respiratory weakness. 
  • Severe hepatic impairment. 
  • Sleep apnoea syndrome. 
  • Unstable myasthenia gravis. 
• Prescribe diazepam with caution to the elderly, people who are debilitated, or people:
  • with a history of alcohol or drug dependence or abuse. 
  • with Mild to moderate hepatic impairment. 
  • With myasthenia gravis.
  • With personality disorders. 
  • With renal impairment. 
  • With respiratory disease. 
  • People who are breastfeeding — the lowest effective doses should be used. Shorter acting agents, such as lorazepam and oxazepam, are preferred, where this is clinically appropriate.

[ABPI, 2019; BNF, 2022; SPS, 2024]

What are the adverse effects associated with diazepam?

• The most common adverse effects of diazepam relate to its sedative effect and include drowsiness, ataxia, fatigue, impaired motor ability, confusion, and decreased alertness. People who are taking benzodiazepines and drive should be given the following advice:
  • The medicine is likely to affect your ability to drive. 
  • Do not drive until you know how the medicine affects you. 
  • It is an offence to drive after taking diazepam if it impairs driving. 
  • It is an offence to drive if you have more than a specified limit of benzodiazepine in your body and you have not been prescribed them.  
    • Roadside saliva screening tests in the UK test for certain drugs that impair driving. If you have a positive roadside drug test for benzodiazepines, the police may ask you to provide a blood sample to measure the amount of benzodiazepine in your body. 
    • If you are found to have more than the specified amount of benzodiazepine in your body, as long as your driving is not impaired, and you are taking your medicine on the advice of a doctor or pharmacist, you will be able to raise a statutory 'medical defence' and the police may not prosecute you. 
  • It may be helpful to keep evidence that you are taking a benzodiazepine in accordance with medical advice with you while you are driving. Suitable evidence may include: your medication box with the pharmacy label on or the other half of your prescription with the list of medicines prescribed by your doctor. 
• Other adverse effects include:
  • Headache, vertigo, tremor, slurred speech, decreased libido, gynaecomastia, and sleep apnoea syndrome.
  • Paradoxical effects, such as talkativeness, excitement, irritability, aggression, and antisocial behaviour. 
  • Tolerance and dependence — over time, users of benzodiazepines can develop tolerance and eventual dependence. For this reason, the National Institute for Health and Care Excellence (NICE) recommends that benzodiazepines should only be used for people with generalized anxiety disorder as a short term measure during crises (for 2–4 weeks). 
  • Withdrawal syndrome — see the CKS topic on Benzodiazepine and z-drug withdrawal.

 [ABPI, 2019; NICE, 2020a; DVLA, 2021; BNF, 2022; HM Government, 2022]  

What are the key drug interactions with diazepam?

• Drug interactions with diazepam include:

  • Alcohol — increased central nervous system depressant effects. Advise the person of the potential effects, and counsel against driving or undertaking other skilled tasks.
  • Cisapride — absorption of diazepam is accelerated. Be aware that sedation may occur more quickly.
  • Cytochrome P450 inhibitors  
    • Azole antifungals (for example, fluconazole, voriconazole) — diazepam levels may be increased. Advise about increased sedation and consider lowering dose of diazepam. 
    • Combined hormonal contraceptives — diazepam clearance may be reduced, and rate of breakthrough bleeding may be increased. Monitor diazepam dose and consider changing to an alternative contraceptive. 
  • HIV protease inhibitors (for example, ritonavir and indinavir) — levels of diazepam may be increased. Concurrent use is contraindicated.
  • Levomepromazine — cases of airways obstruction have been reported with concurrent use of diazepam and intramuscular levomepromazine. Monitor closely for signs of breathing difficulties.
  • Modafinil — levels of diazepam may be increased. Be alert for diazepam adverse effects (such as excessive sedation) and consider a diazepam dose reduction if indicated.
  • Opioids (for example, codeine, buprenorphine) — concurrent use of opioids and benzodiazepines can cause enhanced sedation and respiratory depression, and can result in death. If concurrent use is unavoidable, monitor for increased adverse effects such as sedation and respiratory depression and warn the person about the potential effects and counsel against driving or undertaking other skilled tasks.
  • Phenytoin — serum concentrations of phenytoin may be affected and phenytoin may increase diazepam concentrations. Monitor for reduced diazepam efficacy and phenytoin toxicity (blurred vision, nystagmus, ataxia, or drowsiness); consider monitoring phenytoin concentrations.
  • Rifampicin — levels of diazepam moderately reduced. Monitor for loss of efficacy. 

[ABPI, 2019; Preston, 2023]

What dose of diazepam should I prescribe?

• Prescribe the lowest possible dose for the shortest period of time and review the patient regularly. Treatment should not exceed 2–4 weeks. 
• For anxiety, prescribe 2 mg three times a day. 
  • If needed, the dose can be increased to 15–30 mg daily in three divided doses (half the dose should be prescribed in elderly or debilitated people). 
• For insomnia associated with anxiety, prescribe 5–15 mg at bedtime. 

[ABPI, 2019; BNF, 2022]