Previous changes

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.

August 2023 — reviewed. A literature search was conducted in August 2023 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 minor restructuring. No major changes to the recommendations have been made.

May 2020 — minor update. SSRI drug interactions updated in line with manufacturer's SPC for citalopram.

June 2018 — reviewed. A literature search was conducted in June 2018 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 2013 — reviewed. A literature search was conducted in July 2013 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. There are no major changes to the recommendations.

February 2013 — minor update. The 2013 QIPP options for local implementation have been added to this topic.

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic.

January 2012 — minor update. Lundbeck Ltd, in collaboration with the Medicines and Healthcare products Regulatory Agency (MHRA), has published new safety data regarding the association of citalopram and escitalopram with dose-dependent QT interval prolongation. This topic has been updated to reflect their advice, including new maximum doses. 

August to November 2008 — 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

No new evidence=based guidelines since 1 August 2023.

HTAs (Health Technology Assessments)

No new HTAs since 1 August 2023.

Economic appraisals

No new economic appraisals relevant to England since 1 August 2023.

Systematic reviews and meta-analyses

No new systematic reviews published since 1 August 2023.

Primary evidence

No new primary evidence which reaches the CKS threshold for inclusion published since 1 August 2023.

New policies

No new policies since 1 August 2023.

New safety alerts

No new safety alerts since 1 August 2023.

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 obsessive-compulsive disorder. See more here.

Differential diagnosis

The differential diagnoses of obsessive-compulsive disorder (OCD) include:

• Obsessive-compulsive personality disorder (OCPD) — suggested by a preoccupation with orderliness, details, rules, organisation, or schedules, to the degree that the point of the activity is lost, with absence of obsessions and compulsions, but may involve discomfort if things are sensed not to have been done completely. 
• Body dysmorphic disorder (BDD) — suggested by obsessive preoccupation with a perceived defect in physical appearance.
• Somatic symptom disorder — suggested by excessive thoughts, feelings, or behaviours related to somatic symptoms or associated health concerns.
• Illness anxiety disorder (hypochondriasis) — suggested by a preoccupation with having or acquiring serious illness and excessive health-related behaviours, such as repeatedly checking for signs of illness. May demonstrate maladaptive avoidance, such as avoiding medical appointments.
• Delusional disorder — suggested by a false belief that is firmly sustained and based on incorrect inference about reality. Compulsions may be absent.
• Autism spectrum disorder (including Asperger's syndrome) — suggested by impaired social communication and social interaction with restricted and repetitive patterns of behaviour, interests or activities. Symptoms are present from the early development period. For more information, see the CKS topics on Autism in children and Autism in adults.
• Hoarding disorder — suggested by persistent difficulty in discarding or parting with possessions, regardless of actual value, due to the perceived need to save items and distress associated with discarding them. Where symptoms relate to hoarding only, a diagnosis of hoarding disorder is made.
• Trichotillomania (hair-pulling disorder) — suggested by recurrent pulling out of hair, resulting in hair loss.
• Excoriation (skin-picking) disorder — suggested by recurrent picking of skin, resulting in skin lesions.
• Olfactory reference disorder — suggested by persistent preoccupation with the belief that one is emitting a perceived offensive smell (body odour or breath) that is unnoticeable or only slightly noticeable to others, leading to repeated checking, seeking reassurance, or excessive behaviours relating to this belief.
• Substance-induced or medication-induced obsessive-compulsive disorder — suggested by OCD-type symptoms that are attributable to effects of medication or drug of abuse, and develop during or soon after substance intoxication or withdrawal or after exposure to substance.
• Anxiety disorders — such as phobias or generalized anxiety disorder. There may be recurrent thoughts, avoidant behaviours and repetitive requests for reassurance associated with anxiety disorders, however, these tend to be related to real-life concerns and rituals are not usually present. See the CKS topic Generalized anxiety disorder for more information.
• Depression — there may be ruminations but thoughts are usually mood-congruent and not linked to compulsions. See the CKS topics Depression, Depression in children and Depression - antenatal and postnatal for more information.

ICD-11 and DSM-5 criteria for the diagnosis of obsessive-compulsive disorder

International Classification of Disease (ICD-11) criteria for a diagnosis of obsessive-compulsive disorder (OCD) are [WHO, 2023]:

• The presence of persistent obsessions and/or compulsions.
  • Obsessions are repetitive and persistent thoughts, images or impulses/urges that are experienced as intrusive and unwanted and are commonly associated with anxiety. Typically, the individual attempts to suppress obsessions by performing compulsions. 
  • Compulsions are repetitive behaviours or rituals, including repetitive mental acts, that the individual feels driven to perform in response to an obsession, according to rigid rules, or to achieve a sense of 'completeness'. Compulsions are either not connected in a realistic way to the feared event or are clearly excessive.
• Obsessions and compulsions are time-consuming (e.g. take more than an hour per day), or result in significant distress or significant impairment in personal, family, social, educational, occupational, or other important areas of functioning. If functioning is maintained, it is only through significant additional effort.
• The symptoms or behaviours are not a manifestation of another medical condition or substance or medication, including withdrawal effects.

Diagnostic and Statistical Manual-5 (DSM-5) criteria for OCD are [APA, 2022]:

• The presence of obsessions, compulsions, or both.
  • Obsessions are defined by both of the following:
    • Recurrent and persistent thoughts, urges, or images experienced, at some time during the disturbance, as intrusive and unwanted and in most individuals cause marked anxiety or distress.
    • There is some effort by the affected person to ignore or suppress such thoughts, impulses, or images, or to neutralise them with some other thought or action (i.e., by performing a compulsion).
  • Compulsions are defined by both of the following:
    • Repetitive activities (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession or according to rules that must be applied rigidly.
    • These behaviours or mental acts are performed in order to prevent or reduce anxiety or distress, or prevent some dreaded event or situation. However, they are either clearly excessive or not connected in a realistic way with what they are designed to neutralise or prevent.
• The obsessions and/or compulsions cause clinically significant distress, are time-consuming (take more than 1 hour per day), or cause significant impairment in social, occupational or other important areas of functioning.  
• The obsessions and/or compulsions are not attributable to the physiological effects of a substance or other medical condition.
• The disorder is not better explained by the symptoms of another mental disorder, such excessive worries as in a generalised anxiety disorder, preoccupation with appearance as in body dysmorphic disorder, difficulty discarding or parting with possessions, as in hoarding disorder, hair pulling, as in trichotillomania, repetitive patterns of behaviour as in autism spectrum disorder, ritualised eating behaviour, as in eating disorders etc.

Basis for recommendation

This information is based on the guideline Obsessive-compulsive disorder and body dysmorphic disorder: treatment [NICE, 2005], the International Classification of Disease (ICD-11) [WHO, 2023], the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [APA, 2022] and expert opinion in the BMJ Best Practice topic Obsessive-compulsive disorder [BMJ Best Practice, 2022].

Additional Information

• This list of questions, derived from the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), is included as a guide:
  • How much of your day is occupied by obsessive thoughts or spent performing compulsive acts (mild, less than 1 hour; moderate, 1–3 hours; severe, more than 3 hours)?
  • How much do your obsessive thoughts or compulsive behaviours interfere with your social or work/school functioning (including relationships)?
  • How much distress do your obsessive thoughts cause you? How would you feel if prevented from performing your compulsion(s)? How anxious would you become?
  • How much of an effort do you make to resist the obsessive thoughts or compulsions?
  • How much control do you have over your obsessive thoughts? How strong is the drive to perform the compulsions?
• For the full symptom checklist and for a formal score using this standardized rating scale, see Y-BOCS.
  • Scores: 8 - 15 = Mild OCD, 16 - 23 = Moderate OCD, 24 - 31 = Severe OCD, 32 - 40 = extremely severe OCD.
• The Children's Y-BOCS (CY-BOCS) is similar to the adult version and can be used to assess the nature and severity of symptoms, with the interpretation of the scores being the same.

Basis for recommendation

This information is based on the guideline Obsessive-compulsive disorder and body dysmorphic disorder: treatment [NICE, 2005] and expert opinion in the review articles Obsessive-compulsive disorder: diagnosis and management [Fenske, 2015], Obsessive-compulsive disorder: Advances in diagnosis and treatment [Hirschtritt, 2017], Clinical advances in obsessive-compulsive disorder: a position statement by the International College of Obsessive-Compulsive Spectrum Disorders [Fineberg, 2020] and Obsessive-compulsive disorder [BMJ Best Practice, 2022].

Suicide risk

• The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) reports that suicidal thoughts occur at some point in up to half of individuals with OCD and that suicidal attempts are reported in up to a quarter [APA, 2022].
• Although comorbid depression increases the risk, it has been found there is a significant increase in suicide-related behaviours in people with OCD independently of depressive symptoms and mood instability [Bowen, 2019].

How should I manage a person with obsessive-compulsive disorder?

For all people diagnosed with obsessive-compulsive disorder (OCD)

• Assess the severity and the risk of suicide; consider comorbidity and safeguarding issues.
• Those who should be referred for specialist assessment include: 
  • People assessed as having severe OCD.
  • Those considered at risk of suicide or there is otherwise a risk to life due to OCD symptoms. Refer urgently (same day) to the crisis team if the person is at high risk of suicide. For more information see the section on managing a person at risk of self-harm in the CKS topic on Self-harm. For those in whom admission is thought to be necessary but refuse, see the section on the Mental Health Act in the CKS topic Depression. 
  • Those with severe self-neglect.
  • Those with a significant comorbidity such as substance misuse, severe depression, anorexia nervosa, or schizophrenia.
  • Where healthcare professionals are uncertain about the risk associated with intrusive sexual, aggressive, or death-related thoughts reported by people with OCD. These are common themes in people with OCD of any age and risk can be misinterpreted by those without specific expertise, and where uncertain, the clinician should consult with or refer to a specialist.
  • Where initial treatment or treatments have not led to an adequate response.
  • Those under the age of 18.
• Follow local policy when referring to specialist mental health services, with urgency as dictated by the clinical situation.
• For people being managed in primary care, provide written material about the nature of OCD and its treatment options. Printable leaflets on OCD are available from Mind, The Royal College of Psychiatrists have also produced leaflets on OCD, Perinatal OCD, and OCD in children and young people.

Management in adults

• For adults with mild functional impairment:
  • Recommend a psychological intervention. This is accessed by referral or self-referral to NHS Talking Therapies. Following assessment, low-intensity cognitive-behavioural therapy (CBT), including exposure and response prevention (ERP) may be offered. The format for low-intensity CBT should be up to 10 therapist-hours per person, of one of the following:
    • Brief individual CBT (including ERP) with structured self-help materials.
    • Brief individual CBT (including ERP) by phone.
    • Group CBT (including ERP) which may be for more than 10 hours.
  • If the person has been unable to engage in low-intensity CBT (including ERP) or the response is inadequate, treat as for moderate functional impairment.
• For adults with moderate functional impairment:
  • Offer the choice of intensive CBT including ERP (accessed by referral or self-referral to NHS Talking Therapies), or a selective serotonin reuptake inhibitor (SSRI) (see below). 
  • Consider prescribing clomipramine (as an alternative first-line drug treatment to an SSRI) if the person prefers clomipramine or has had a previous good response to it, or if an SSRI is contraindicated. For more information on prescribing clomipramine, please see the relevant section in Prescribing information.
  • If you are not confident of your assessment of moderate functional impairment or there is an inadequate response to initial treatment, refer to the secondary care mental health team.
• For adults with severe functional impairment:
  • Refer to the secondary care mental health team for assessment.
  • Whilst awaiting assessment:
    • Consider offering combined treatment with an SSRI (see below) and CBT (including ERP).
    • Consider prescribing clomipramine (as an alternative first-line drug treatment to an SSRI) if the person prefers clomipramine or has had a previous good response to it, or if an SSRI is contraindicated.
• When prescribing an SSRI:
  • Escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline are all licensed for the treatment of OCD in adults. Citalopram can also be prescribed as a treatment for OCD, but this is an unlicensed use. 
  • Discuss the potential for adverse effects and withdrawal symptoms before drug treatment is initiated. Explain that adverse effects early in treatment with an SSRI may include increased anxiety, agitation, and sleeping problems.
  • Advise the person that treatment with an SSRI usually requires a higher dose and a longer duration of treatment (at least 12 weeks) for an initial response.
  • Be aware that in a minority of people under 30 years of age, SSRIs are associated with an increased risk of suicidal thinking and self-harm. Anyone in this age group receiving an SSRI should therefore be seen within 1 week of first prescribing, and the risk of suicidal thinking and self-harm should be monitored closely until the risk is no longer considered significant. 
  • When adults with comorbid depression are assessed to be at a high risk of suicide, the use of additional support such as more frequent direct contact with primary care staff or telephone contacts should be considered, particularly during the first weeks of treatment. For people at high risk of suicide, a limited quantity of medication should be prescribed.
  • Adults started on SSRIs who are not considered to be at increased risk of suicide or self-harm should be monitored closely — the effectiveness and adverse effects of the drug should ideally be reviewed every 2 to 4 weeks during the first 3 months of treatment and every 3 months thereafter. Dose adjustment may be required. Bear in mind that an absence of clinical benefit within four weeks suggests that a response to unchanged treatment is unlikely, but that the full efficacy of the drug may take up to 12 weeks to be realised.
  • For more information on prescribing an SSRI, please see the relevant sections in Prescribing information.
• When prescribing clomipramine, be aware of the need to monitor patients for the emergence of other psychiatric symptoms, as well as the emergence of suicidality. Advise the person to report such symptoms immediately.
  • Prescribe small quantities at a time for people considered at significant risk of suicide due to its toxicity in overdose. Monitor regularly until the risk of suicide has subsided.
  • For those considered at risk of suicide and adults below the age of 25, review within a week of initiating, and then as often as needed, but no later than 4 weeks after initiating clomipramine.
  • For more information on prescribing clomipramine, please see the relevant section in Prescribing information.

Management in pregnancy

• If a pregnant woman requires treatment for OCD:
  • When considering the need for drug treatment for OCD in pregnancy, consider seeking the opinion of a specialist in perinatal mental health.
  • It is necessary to balance the risk of harm to the foetus from medication against the risk to both the mother and foetus from untreated illness.
  • Further information on the use of specific medicines in pregnancy is available from the UK teratology information service, the manufacturers' product information, and the British National Formulary (BNF).
  • Data is limited but current advice includes:
    • There is no robust evidence to suggest one SSRI is safer than another.
    • There may be a small risk of foetal cardiovascular malformation associated with SSRI treatment in pregnancy, but this is not confirmed.
    • There may be a risk of neonatal withdrawal syndrome if the mother is taking SSRIs in the weeks prior to delivery. (Infants should be delivered in hospital and monitored.)
    • There may be a small risk of persistent pulmonary hypertension in the newborn where there is SSRI exposure beyond 20 weeks of gestation.
    • There may be an increased risk of postpartum haemorrhage where SSRIs are used in the month prior to delivery.
    • Where treatment with an SSRI is necessary, the lowest effective dose should be used.
    • The manufacturer of clomipramine does not recommend its use in pregnancy or in women of childbearing potential not using contraception, although data is limited.

Management in children and young people

• For children and young people (under the age of 18 years) diagnosed with OCD with any level of functional impairment:
  • Refer to Child and Adolescent Mental Health Services (CAMHS).
    • Those with mild OCD will be offered guided self-help (a self-help programme with support, guidance and encouragement from a mental health professional).
    • Those with moderate to severe functional impairment and those with mild functional impairment for whom guided self-help has been ineffective or refused, will be offered CBT (including ERP) that involves the family and carers and is age-appropriate. If psychological treatment is declined or ineffective, or they are unable to engage with it, an SSRI may be considered.
• Note: a selective serotonin reuptake inhibitor (SSRI) should only be prescribed to people under 18 years of age following assessment and diagnosis by a child and adolescent psychiatrist. The specialist should also be involved in decisions about dose changes and discontinuation and is likely to be key in arranging active monitoring of the person's symptoms, functioning, and response to treatment (if applicable) at intervals determined by clinical judgment.

Contraindications and cautions

Contraindications

• For all SSRIs: Do not prescribe SSRIs to people:
  • In a manic phase of bipolar disorder.
  • With poorly controlled epilepsy or new onset seizures.
  • With hypersensitivity to the active substance or any of the excipients. 
• Do not prescribe citalopram or escitalopram to people with:
  • Known QT-interval prolongation or congenital long QT syndrome, or those using other medicinal products that are known to prolong the QT-interval.

Cautions

• For all SSRIs: Prescribe SSRIs with caution to people:
  • Who are under the age of 18. (Suicide related behaviours more common in the younger population. Fluvoxamine and sertraline are the only SSRIs licensed for obsessive-compulsive disorder in this age group.)
  • Who are under the age of 25. Suicidal behaviour related to SSRIs is more common in young adults under the age of 25.
  • Who have cardiac disease.
  • Who have epilepsy (discontinue if convulsions develop).
  • 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, NSAIDS or aspirin) may also be at risk. Consider prescribing a gastroprotective drug in these circumstances.
  • Who have diabetes mellitus.
  • With a history of mania.
  • Who have suicidal thoughts or a history of suicide-related events (Monitor closely, and alert patients and caregivers to the risk and the need to seek urgent medical advice if there is an increase in worsening, suicidal behaviour or thoughts or change to behaviour.)
  • Who have susceptibility to angle-closure glaucoma.
  • Who are at risk of hyponatraemia (particularly the elderly, and those on medication which may cause hyponatraemia.)
  • Undergoing concurrent electroconvulsive therapy.
• Prescribe fluoxetine and citalopram, and sertraline with caution to people with hepatic impairment — a lower or less frequent dose should be considered and liver function should be closely monitored.
• Prescribe fluvoxamine and paroxetine with caution to people with hepatic or renal impairment — prescribe a low starting dose and monitor carefully.
• Prescribe citalopram and escitalopram with caution to those with susceptibility to QT-interval prolongation. For example, a family history of QT prolongation or other clinical conditions that predispose to arrhythmias (e.g., hypokalaemia and hypomagnesemia, bradycardia, acute myocardial infarction or uncompensated heart failure), or concomitant use with medicinal products known to induce hypokalaemia and hypomagnesemia, QT prolongation, and/or torsade de pointes — cases of QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported during the post-marketing period. If signs of cardiac arrhythmia occur during treatment with an SSRI, the treatment should be withdrawn and an ECG should be performed.

[EMC, 2020; EMC, 2021b; EMC, 2021c; BNF, 2023; BNFC, 2023; EMC, 2023a; EMC, 2023b; EMC, 2023c]

Adverse effects

• The most common adverse effects associated with use of an SSRI include:
  • Gastrointestinal effects — these are dose-related and include nausea, vomiting, abdominal pain, abnormal appetite, altered taste, dyspepsia, constipation, and diarrhoea.
  • Central nervous system effects — including dizziness, confusion, impaired concentration, anxiety, insomnia, headache, and tremor. Intensified anxiety may occur at the start of treatment and usually subsides within the first two weeks.
  • Drowsiness — may impair performance of skilled tasks such as driving and operating machinery.
    • Advise the person that it is illegal in England and Wales to drive while taking a prescribed drug if it impairs driving. The Driver and Vehicle Licensing Agency (DVLA) document Assessing Fitness to Drive includes antidepressants in the list of drug groups which may require consideration, but acknowledges that SSRIs are less sedating than tricyclics. It recommends that advice for individual driving safety should be considered carefully for all antidepressants [DVLA, 2022].
  • Sexual dysfunction — which may persist after discontinuation. Side effects which can occur include loss of libido, ejaculation delay or failure, premature or retrograde ejaculation, erectile dysfunction, and anorgasmia.
  • Weight changes.
  • Lethargy, weakness, fatigue or malaise.
  • Blurred vision.
  • Tinnitus.
• Other adverse effects include:
  • 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]).
  • 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 [MHRA, 2014]. 
  • Hyponatraemia — risk factors for developing hyponatraemia include a history of hyponatraemia, extreme old age (greater than 80 years of age), female sex, low body weight, diuretics, diabetes mellitus, hypertension, reduced renal function, volume depletion, and chronic obstructive pulmonary disease.
    • Monitor the person for signs and symptoms of hyponatraemia (such as dizziness, lethargy, nausea, confusion, cramps, and seizures).
  • Akathisia — characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In people who develop these symptoms, increasing the dose may be detrimental.
  • Increased suicide risk — this is most likely in younger people (less than 25 years of age) when starting an SSRI.
    • Monitor people carefully during the first few weeks of SSRI treatment; in particular, be alert for signs of suicidal ideation, akathisia, and increased anxiety and agitation. 
  • Discontinuation symptoms (such as dizziness, sensory disturbances [including paraesthesia], sleep disturbances [including insomnia and intense dreams], agitation or anxiety, nausea and/or vomiting, tremors, 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. 
    • Discontinuation symptoms do not affect everyone and vary in type and severity between individuals.
    • Generally, these symptoms are mild to moderate; however, in some people, they may be severe.
    • They usually occur within the first few days of discontinuing treatment.
    • Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2 – 3 months or more).
    • It is therefore advised that an SSRI 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 compared with other selective serotonin reuptake inhibitors.
  • For citalopram and escitalopram, QT prolongation and/or ventricular arrhythmias; especially in women, people with hypokalaemia, or people with pre-existing QT prolongation or other cardiac disease.
  • Hyperprolactinaemia is an effect of unknown frequency with Citalopram use.

[EMC, 2020; EMC, 2021b; EMC, 2021c; NICE, 2022; BNF, 2023; BNFC, 2023; EMC, 2023a; EMC, 2023b; EMC, 2023c; EMC, 2023d; EMC, 2024]

Drug interactions

Key drug interactions with SSRIs as a class include:

• Serotonergic drugs — increased risk of serotonergic effects and increased risk of serotonin syndrome. This includes monoamine oxidase inhibitors (MAOIs — see below), lithium, opioids (tramadol, buprenorphine, fentanyl, pethidine), duloxetine, St John's Wort, sumatriptan and other triptans, tryptophan,  vortioxetine and other SSRIs including dapoxetine.
  • The manufacturer of dapoxetine advises SSRIs should not be started until 1 week after stopping dapoxetine and to avoid dapoxetine for 2 weeks after stopping SSRIs.
  • Lithium — increased risk of CNS effects when SSRIs are given with lithium (lithium toxicity reported).
    • Advise the person to be alert for symptoms such as decreased appetite, diarrhoea, vomiting, ataxia, nystagmus, dysarthria, confusion, and seizures. Consider frequent monitoring of lithium levels.
• MAOIs — CNS effects of SSRIs including serotonin syndrome are increased by MAOIs (risk of serious toxicity and sometimes fatal reactions). None are recommended and some are contraindicated in combination. Any co-prescribing, or switching between these groups of drugs requires extreme caution. Manufacturers provide individual recommendations for regimes for discontinuing an MAOI and starting an SSRI and vice versa. This includes:
  • Irreversible, non-selective MAOIs (eg iproniazid).
  • Reversible, non-selective MAOIs (such as linezolid).
  • Reversible, selective MAO-A inhibitors (such as moclobemide and methylene blue).
  • Irreversible, selective MAO-B inhibitors (such as selegiline and rasagiline). 
• Antiepileptics — SSRIs may antagonise anticonvulsant effect of some antiepileptics (convulsive threshold lowered). Caution is also required when used in combination with other agents which lower the seizure threshold (such as other antidepressants, neuroleptics, mefloquine, chloroquine, bupropion, tramadol)  as there is an increased risk of seizures.
• Aspirin, oral anticoagulants, and NSAIDs — increased risk of bleeding.
• Coumarins — SSRIs possibly enhance anticoagulant effect of coumarins.
  • Consider frequent monitoring of the 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 antagonised by cyproheptadine.
• Pimozide — SSRIs possibly increase plasma concentration of pimozide (increased risk of ventricular arrhythmias—avoid concomitant use).
• Tricyclic antidepressants — SSRIs increase the plasma concentration of some tricyclics.
• Alcohol — all manufacturers recommend that patients are advised to avoid alcohol use while taking SSRIs, although no interactions or potentiation has been demonstrated.

Key additional drug interactions with specific SSRIs include:

• Citalopram and escitalopram
  
  • Drugs that prolong the QT interval (such as Class IA and III antiarrhythmics, antipsychotics [phenothiazine derivatives, pimozide, haloperidol], tricyclic antidepressants, certain antimicrobial agents [moxifloxacin, erythromycin, pentamidine], anti-malaria treatment particularly halofantrine, and certain antihistamines [astemizole, mizolastine].
  • CYP2C19 inhibitors (omeprazole, esomeprazole, fluconazole, fluvoxamine, lansoprazole, ticlopidine) and cimetidine — may increase levels of citalopram and dose reduction may be necessary.
  • Propafenone, flecainide, metoprolol, desipramine, clomipramine, nortriptyline, risperidone, thioridazine and haloperidol — co-administration may lead to increased plasma levels of these drugs.
• Fluoxetine:
  • The manufacturer recommends considering the long elimination half-life of fluoxetine when considering interactions, particularly when switching to another antidepressant.
  • Mequitazine — increased risk of mequitazine adverse events (such as QT prolongation) because of an inhibition of its metabolism by fluoxetine.
  • Metoprolol used in cardiac failure — increased risk of metoprolol adverse events including excessive bradycardia, because of inhibition of its metabolism by fluoxetine.
  • Drugs that cause QT interval prolongation (such as Class IA and III antiarrhythmics, antipsychotics [phenothiazine derivatives, pimozide, haloperidol], tricyclic antidepressants, certain antimicrobial agents [moxifloxacin, erythromycin IV, pentamidine], anti-malaria treatment particularly halofantrine, certain antihistamines [astemizole, mizolastine], — pharmacokinetic and pharmacodynamic studies with fluoxetine have not been performed. The manufacturer advises that an additive effect of fluoxetine and these medicinal products cannot be excluded. 
  • Phenytoin — changes in blood levels (and in some cases, toxicity) have been observed in combination with fluoxetine — consider using conservative titration schedules and monitor clinical status.
  • Drugs that cause hyponatraemia such as diuretics, desmopressin, carbamazepine and oxcarbazepine, as fluoxetine also causes hyponatraemia.
  • Procyclidine — daily administration of paroxetine significantly increases its plasma levels. If anticholinergic effects are seen, the dose of procyclidine should be reduced.
  • Tamoxifen — interaction may cause significant reduction of plasma levels of tamoxifen and reduced efficacy.
• Fluvoxamine:
  • Terfenadine, astemizole, cisapride and sildenafil — plasma concentrations may be increased resulting in a higher risk for side effects.
  • Tacrine, theophylline, methadone, mexiletine, phenytoin, carbamazepine and cyclosporine — co-administration with fluvoxamine should be carefully monitored.
  • Midazolam, alprazolam, and diazepam — plasma levels are likely to be increased when co-administered with fluvoxamine. The dosage of these benzodiazepines should, therefore, be reduced during co-administration.
  • Ropinirole — plasma concentrations may be increased in combination with fluvoxamine, thus increasing the risk of overdose. Surveillance and reduction in the dosage of ropinirole during fluvoxamine treatment and after its withdrawal may, therefore, be required.
  • Propranolol — as plasma concentrations are increased in combination with fluvoxamine, the propranolol dose may need to be lowered.
  • Clopidogrel — avoid concomitant use if possible as concentrations of clopidogrel may be lowered.
• Paroxetine:
  • Metoprolol — increased risk of metoprolol adverse events because of inhibition of its metabolism by paroxetine.
  • Tamoxifen — paroxetine is a potent inhibitor of the liver enzyme CYP2D6 and may reduce the plasma concentration of tamoxifen, leading to reduced efficacy.
  • Risperidone, atomoxetine, flecainide, propafenone, thioridazine, perphenazine, clomipramine, nortriptyline, desipramine,  — paroxetine may inhibit their metabolism and increase their plasma concentrations.
  • Carbamazepine, rifampicin, phenobarbital, phenytoin, fosamprenavir, ritonavir — may alter plasma concentration of paroxetine. The manufacturer advises no initial dose adjustment is necessary, but thereafter may be guided by clinical effect.
  • Pravastatin — co-administration may lead to an increase in blood glucose levels. People with diabetes mellitus receiving both drugs may require dosage adjustment of oral hypoglycaemic agents and/or insulin. 
  • Procyclidine — co-administration may lead to an increase in procyclidine levels and subsequently a higher risk of anti-cholinergic side effects. The dose of procyclidine may need to be reduced.
• Sertraline
  • Propafenone and flecainide — co-administration may lead to increased plasma levels of these drugs.
  • Atenolol — co-administration causes a substantial decrease in sertraline clearance.
  • Drugs that prolong the QT interval (such as Class IA and III antiarrhythmics, antipsychotics [phenothiazine derivatives, pimozide, haloperidol], tricyclic antidepressants, certain antimicrobial agents [moxifloxacin, erythromycin, pentamidine], anti-malaria treatment particularly halofantrine, and certain antihistamines [astemizole, mizolastine].
  • Grapefruit juice — may increase sertraline levels. The manufacturer recommends avoiding.

[EMC, 2020; EMC, 2021b; EMC, 2021c; EMC, 2021d; BNF, 2023; EMC, 2023a; EMC, 2023b; EMC, 2023c]

Dosing information

Initial dosage and titration of selective serotonin reuptake inhibitors (SSRIs):

• Citalopram (unlicensed):
  • Initial dose 20 mg each day.
  • If necessary, increase gradually to a maximum of 40 mg daily (20 mg in the elderly and in those with reduced hepatic function).
• Escitalopram:
  • Initial dosage is 10 mg once daily (5 mg once daily in the elderly or in those with mild or moderate hepatic impairment).
  • If necessary, the dose may be increased to a maximum of 20 mg daily (10 mg daily in the elderly).
• Fluoxetine:
  • Initial dose 20 mg once a day, in the morning. In those with hepatic impairment, consider a lower or less frequent dose (20 mg alternate days).
  • If necessary, increase gradually to a maximum of 60 mg daily.
• Fluvoxamine:
  • Initial dose 50 mg once a day, at bedtime.
  • Increase to 100 mg after several weeks, and then gradually in steps of 50 mg to a maximum of 300 mg/day if necessary.
  • Usual maintenance dose is 100–300 mg/day (over 150 mg in divided doses).
  • For those aged 8 to 17, the starting dose is 25 mg per day, increasing in 25 mg increments every 4 to 7 days as tolerated until an effective dose is achieved. Doses above 50 mg should be given in two divided doses. The maximum dose in children is 200 mg per day.
  • It is only advisable to use fluvoxamine to treat OCD in children and young people where there has been assessment, diagnosis and advice from a child and adolescent psychiatrist, who should also be involved in decisions about dose changes and discontinuation [NICE, 2005].
  • For people with hepatic or renal impairment, start on a low dose and monitor carefully.
• Paroxetine:
  • Initial dose 20 mg once a day.
  • If necessary, increase gradually in steps of 10 mg to 40 mg daily. The manufacturer's recommended dose is 40 mg per day.
  • If after some weeks on 40 mg/day an insufficient response is seen, a gradual dose increase up to a maximum of 60 mg/day can be considered (maximum 40 mg per day in the elderly).
  • Use doses in the lower end of the dose range for those with hepatic or severe renal impairment.
• Sertraline:
  • Initial dose 50 mg once a day, in the morning or evening.
  • If necessary, increase gradually in steps of 50 mg to a maximum of 200 mg/day.
  • Usual dose range is 50–200 mg daily.
  • For those aged 6 to 12, the initial dose is 25 mg once daily, which may be increased to 50 mg once daily after one week. For those aged 13 to 17, the initial dose is 50 mg once daily. Subsequent increases, if needed, may occur in 50mg increments over a period of some weeks, up to a maximum of 200 mg daily. However, the manufacturer recommends considering body weight when increasing the dose above 50 mg.
  • It is only advisable to use sertraline to treat OCD in children and young people where there has been assessment, diagnosis and advice from a child and adolescent psychiatrist, who should also be involved in decisions about dose changes and discontinuation [NICE, 2005].
  • Use a lower or less frequent dose for those with mild or moderate hepatic impairment.

[EMC, 2020; EMC, 2021b; EMC, 2021c; BNF, 2023; BNFC, 2023; EMC, 2023a; EMC, 2023b; EMC, 2023c]

Contraindications and cautions

• Do not prescribe clomipramine to people with:
  • Acute porphyrias.
  • Recent myocardial infarction, any degree of heart block, or other cardiac arrhythmias.
  • Severe liver disease.
  • Concurrent administration with monoamine oxidase inhibitors or within 3 weeks of start or cessation of therapy.
  • Concomitant treatment with selective, reversible MAO-A inhibitors, such as moclobemide.
  • Narrow-angle glaucoma.
  • Retention of urine.
  • Mania.
  • Hypokalaemia — hypokalaemia should be treated before initiating treatment with clomipramine.
• Clomipramine should not be used for children and adolescents under the age of 18.
• Prescribe clomipramine with caution to people with:
  • Hepatic or renal impairment — in people with hepatic and renal disease, periodic monitoring of hepatic enzyme levels and renal function is recommended.
  • Cardiovascular disorders, especially cardiovascular insufficiency, conduction disorders, (e.g. atrioventricular block grades I to III), and arrhythmias — check blood pressure and conduct an electrocardiogram (ECG) before prescribing clomipramine for adults at significant risk of cardiovascular disease.
  • A history of suicide-related events, those with significant suicidal ideation, and those under the age of 25 — risk may increase in early stages of treatment. Monitor closely until risk subsides, and alert patients and caregivers to report worsening symptoms, suicidal thoughts, or suicidal behaviour.
  • Epilepsy or other predisposing factors for seizure such as brain damage of varying aetiology, concomitant use of neuroleptics, withdrawal from alcohol or drugs with anticonvulsive properties (e.g. benzodiazepines) — clomipramine reduces the seizure threshold and extreme caution should, therefore, be exercised.
  • A history of increased intraocular pressure, narrow-angle glaucoma, urinary retention or symptoms of bladder neck obstruction, e.g. diseases of the prostate, such as prostatic hypertrophy— the anticholinergic properties of clomipramine can exacerbate these conditions.
  • Tumours of the adrenal medulla (e.g. phaeochromocytoma, neuroblastoma) — administration of clomipramine may provoke hypertensive crises.
  • Hyperthyroidism or concomitant treatment with thyroid preparations — aggravation of unwanted cardiac effects may occur.
  • Chronic constipation — tricyclic antidepressants may cause paralytic ileus, particularly in people who are older and/or bedridden.
  • A history of bipolar disorder. (Stop clomipramine if a patient on this medication enters a manic phase.)
• Note: monitoring of cardiac function and ECG and monitoring for psychiatric side effects is indicated in elderly people who are more susceptible to side effects.
• Note: Abrupt withdrawal should be avoided. Taper when discontinuing.

[EMC, 2021a; BNF, 2023]

Adverse effects

The most common adverse effects of clomipramine include:

• Increased or decreased appetite.
• Psychiatric effects — restlessness, confusion, disorientation, hallucinations (particularly in older patients and those with Parkinson's disease), anxiety, agitation, sleep disorder, mania, hypomania, aggression, depersonalisation, aggravation of depression, insomnia, nightmares, and delirium.
• CNS effects — dizziness, tremor, headache, myoclonus, somnolence, speech disorder, paraesthesia, hypertonia, dysgeusia, memory impairment, disturbance in attention.
  • Advise the person that it is illegal in England and Wales to drive while taking a prescribed drug if it impairs driving [DVLA, 2022].
• Eye disorders — accommodation disorder, blurred vision, mydriasis.
• Cardiac disorders — sinus tachycardia, palpitation, orthostatic hypotension, clinically irrelevant ECG changes (e.g. ST and T changes) in people of normal cardiac status.
• Gastrointestinal disorders — nausea, dry mouth, constipation, vomiting, diarrhoea.
• Other — fatigue, tinnitus, hot flush, yawning, hyperhidrosis, allergic dermatitis (skin rash, urticaria), photosensitivity reaction, pruritus, muscular weakness, micturition disorder, urinary retention, libido disorder, erectile dysfunction, galactorrhoea, breast enlargement, weight gain.

[EMC, 2021a; BNF, 2023]

Drug interactions

Key drug interactions with clomipramine include:

• MAOIs — do not give clomipramine for at least 3 weeks after discontinuation of treatment with MAO inhibitors as there is a risk of severe symptoms consistent with Serotonin Syndrome such as hypertensive crisis, hyperpyrexia, myoclonus, agitation, seizures, delirium and coma). The same applies when giving a MAO inhibitor after previous treatment with clomipramine. In both instances, the treatment should initially be given in small gradually increasing doses and its effects monitored. 
•  Serotonergic drugs —  increased risk of serotonergic effects including risk of serotonin syndrome. Concurrent use is not recommended for SSRIs including dapoxetine, SNRIs, tricyclic antidepressants and lithium. 
  • Fluoxetine, paroxetine, sertraline, and fluvoxamine — may increase plasma concentrations of clomipramine with corresponding adverse effects.
  • For fluoxetine, a wash-out period of two to three weeks is advised before commencing clomipramine treatment, with clomipramine wash-out also required if fluoxetine is subsequently to be administered.
  • Opioids, buprenorphine, triptans, St John's wort — use cautiously as the combination increases the risk of serotonin syndrome.
• Diuretics — concurrent use may lead to hypokalaemia, which increases the risk of QTc prolongation and torsades de pointes. Concurrent use is not recommended.
• Quinidine — should not be given concurrently with clomipramine.
• Terbinafine, cimetidine, methylphenidate, sodium valproate  — co-administration may lead to increased plasma levels of clomipramine.
• Phenothiazines — may result in increased plasma levels of clomipramine, a lowered convulsion threshold, and seizures. Concurrent use of thioridazine may produce severe cardiac arrhythmias.
• Rifampicin, anticonvulsants (such as barbiturates, carbamazepine, phenobarbital and phenytoin), cholestyramine or colestipol, St. John's wort — concurrent use may decrease plasma levels of clomipramine.
• Anticholinergic agents (such as phenothiazines, antiparkinsonian agents, antihistamines, atropine, and biperiden),  CNS depressants (such as barbiturates, benzodiazepines, or general anaesthetics), sympathomimetic drugs, (such as adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, and phenylpropanolamine contained in local and general anaesthetic preparations and nasal decongestants) — co-administration may potentiate the effects of these drugs. Caution is therefore advised.
• Coumarins — clomipramine possibly enhances the anticoagulant effect of coumarins.
  • Consider frequent monitoring of the INR. Any change in the person's clinical condition, particularly liver disease, intercurrent illness, or drug administration, necessitates more frequent monitoring of the INR. 
• Guanethidine, betanidine, reserpine, clonidine and alpha-methyldopa — clomipramine may diminish or abolish the antihypertensive effects of these drugs. People requiring co-medication for hypertension should, therefore, be given antihypertensives of a different type (e.g. vasodilators, or beta-blockers).
• Drugs that prolong the QT interval (such as such as certain antiarrhythmics [including quinidine, disopyramide, procainamide, amiodarone and sotalol], tricyclic antidepressants [such as amitriptyline], certain tetracyclic antidepressants [such as maprotiline], certain antipsychotic medications [such as phenothiazines and pimozide], certain antihistamines [such as terfenadine]; lithium, quinine,  and pentamidine) — co-administration increases the risk of QTc prolongation and torsades de pointes.
  • Drugs that increase the plasma levels of clomipramine (including antiarrhythmics, certain antidepressants including SSRIs, tricyclic antidepressants and moclobemide; certain antipsychotics; β-blockers; protease inhibitors, opiates, cimetidine, and terbinafine) may also increase the risk of QTc prolongation and torsades de pointes if co-administered.
• Non-steroidal anti-inflammatory drugs — co-administration may lead to an increased risk of bleeding.
• Analgesics — possible increased side effects with nefopam; possible increased risk of convulsions with tramadol; possible increased sedation with opioid analgesics; increased risk of ventricular arrhythmias with levacetylmethadol.
• Dopaminergics — concomitant use with entacapone should be avoided; central nervous system toxicity has been reported with selegiline.
• Muscle relaxants — concomitant use may enhance the muscle relaxant effect of baclofen.
• Grapefruit, grapefruit juice or cranberry juice (also cigarette smoking) — may increase the plasma concentrations of clomipramine.

[EMC, 2021a; BNF, 2023]

Dosing information

• Initially, prescribe 25 mg each day (or 10 mg daily in the elderly).
• If there are no significant adverse effects:
  • Increase gradually over 2 weeks to 100–150 mg daily (increase more slowly in the elderly).
  • At 4–6 weeks, if there is an inadequate treatment response, increase gradually up to a maximum dose of 250 mg daily.

[EMC, 2021a; BNF, 2023]