Clinical Guideline / Formulary Document Pharmacy Department Medicines Management Services

Clinical Guideline / Formulary Document Pharmacy Department Medicines Management Services ANXIETY DISORDERS This guideline covers a range of anxiety disorders, including generalised anxiety disorder, social anxiety disorder, post-traumatic stress disorder, panic disorder, obsessive compulsive disorder and body dysmorphic disorder. Anxiety disorders often co-exist with other psychological symptoms, especially depressive symptoms. Psychological and pharmacological therapies are used to treat anxiety disorders. NICE guidelines suggest a stepped care* approach for managing of anxiety disorders (*Adapted from NICE CG113 Anxiety) Step 1: Identification and assessment; education about anxiety disorder and treatment options; active monitoring. Step 2: Use of low-intensity psychological interventions: individual non-facilitated self-help, individual guided self-help and psychoeducational groups Step 3: For inadequate response to step 2 interventions or marked functional impairment. Choice of a high-intensity psychological intervention (CBT/applied relaxation) or a drug treatment. Step 4: Complex treatment-refractory anxiety disorder and very marked functional impairment or a high risk of self-harm; requiring highly specialist treatment Pharmacological Treatments Pharmacological treatment of anxiety disorders should be considered for severe and persistent symptoms which result in occupational and social disability Psychological interventions should be offered to service users who prefer non-pharmacological treatment or have not benefited from or are unable to engage with pharmacological interventions. The choice of initial treatment should be guided by preference, risks and benefits, side effects, prior treatment history, presence of other physical and psychiatric conditions, suicide risk, potential drug interactions and cost. Discuss the condition and treatment options fully and provide written information. Selective Serotonin Reuptake Inhibitors (SSRIs) are effective for a range of anxiety disorders and are suitable first-line treatments. Inform service users prescribed antidepressants about a delayed onset of effect (at least 2 weeks), likely length of treatment and the need to take medication as prescribed. Pregabalin is licensed for use in Generalised Anxiety Disorder (GAD). Buspirone is licensed for the short-term management of anxiety. People with an anxiety disorder should not be prescribed benzodiazepines or antipsychotics unless specifically indicated. Decisions about off-label use of medications for anxiety disorders should be led by guidelines, evidence from scientific literature and clinical experience. Informed consent to off-label use should be obtained and documented. Response to treatment should be assessed and recorded at each review and treatment adjusted if needed. Safety Warnings Antidepressants are associated with an initial worsening of anxiety/agitation and an increased risk of suicidal thinking and behaviour. Monitor closely particularly at the start of treatment and when the dose is changed. Anxiety Disorders Next Review: Jan 2019 1

Discontinue antidepressants gradually. Abrupt discontinuation (sometimes reduced or missed doses) of antidepressants can lead to withdrawal symptoms e.g. dizziness, paraethesias, nausea, headaches, sweating, anxiety and sleep disturbances. Use antidepressants with care in glaucoma, bipolar disorders, prostate hypertrophy, bleeding disorders and seizures. Hyponatraemia has been associated with all antidepressants and should be considered in all those who develop drowsiness, confusion, or convulsions while on antidepressants. SSRIs can increase risk of bleeding. Caution is required in older adults and when used in combination with NSAIDS, aspirin or anticoagulants. SSRIs can increase risk of falls and osteoporotic fractures in people over 50 years. Serotonin syndrome (agitation, confusion, tremor, hypereflexia, myoclonus and hyperthermia) can occur with serotonergic drugs and requires emergency management. Benzodiazepines are associated with physical and psychological dependence when taken regularly for more than a few weeks. Avoid prolonged use. Withdrawal of a benzodiazepine should be gradual because abrupt withdrawal may produce confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. A paradoxical increase in hostility and aggression may be reported by patients taking benzodiazepines. The effects range from talkativeness and excitement to aggressive and antisocial acts. Adjustment of the dose (up or down) sometimes attenuates the impulses. Increased anxiety and perceptual disorders are other paradoxical effects. Cases of misuse, abuse and dependence have been reported with pregabalin. Psychotropic drugs may impair the mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery, the patient should be cautioned accordingly. Adverse Effects and Interactions SSRIs are better tolerated and safer in overdose than other antidepressants. Common side effects of SSRIs are headache, nausea, and anxiety/agitation, especially when starting treatment (usually settle on continued treatment). Other side effects are insomnia, tremor, akathisia, sweating, paraethesias, sexual dysfunction, including diminished libido and difficulty with erection and orgasm, muscle/joint pain, weight gain and manic or psychotic symptoms. Tricyclic antidepressants have similar efficacy to SSRIs but are more likely to be discontinued because of side-effects and are toxic in overdose. Common side effects of tricyclics include anxiety, drowsiness, dizziness, agitation, confusion, anticholinergic effects (dry mouth, constipation, urinary retention and blurred vision); cardiovascular effects (hypotension, tachycardia, arrhythmias and other ECG changes - baseline ECG is advised, where appropriate); hepatic effects, changes in blood sugar, increased appetite, weight gain and sexual dysfunction. Monoamine Oxidase Inhibitors (MAOIs) can have dangerous interactions with some foods and drugs, and should be reserved for initiation by consultants. Service users prescribed MAOIs require careful monitoring (blood pressure) and advice on dietary and drug interactions. When changing antidepressants, a suitable washout period (usually at least 14 days) should be allowed before or after using MAOIs. All people prescribed antidepressants, should be informed, at the time that treatment is initiated, of potential side effects and discontinuation/withdrawal symptoms (particularly with paroxetine). Monitor for akathisia, anxiety, agitation, increased suicide risk and other side effects. People prescribed antidepressants should be reviewed after 2 weeks and regularly thereafter eg every 2 4 weeks in the first 3 months and at greater intervals if response is good. People considered to be at increased suicide risk should be seen after 1 week and frequently thereafter until the risk is no longer considered significant. Due to risk of dependence, tolerance, withdrawal and rebound symptoms, benzodiazepines should be reserved for short-term use (two to four weeks only) at the lowest effective dose for anxiety that is severe, disabling, or causing unacceptable distress. Benzodiazepines can cause Anxiety Disorders Next Review: Jan 2019 2

sedation, fatigue, ataxia, slurred speech, and risk of falls and fractures. Long term use can cause memory impairments, dependence, impaired alertness and impaired ability to perform skilled tasks (e.g. driving) Mirtazapine has few antimuscarinic effects, but causes sedation during initial treatment and is associated with weight gain and blood dyscrasias. Antipsychotics may be used with caution in anxiety with agitation or psychotic symptoms. Pregabalin treatment has been associated with dizziness and somnolence. There have also been post-marketing reports of loss of consciousness, confusion and mental impairment. Increased appetite, increased weight, suicidal thoughts and behavior have been reported. Other adverse effects reported include: vision-related effects and gastrointestinal effects. Specific Phobias Simple or specific phobias are usually unresponsive to pharmacological treatments and respond better to behavioural therapy, although paroxetine or benzodiazepines may be considered for disabling phobias unresponsive to psychological approaches General Anxiety Disorder (GAD) A stepped-care approach is recommended by NICE for the management of GAD, offering the least intrusive, most effective intervention first with non-drug interventions the mainstay of treatment for many people with GAD. A high-intensity psychological intervention (e.g. CBT) or drug treatment is recommended for people with GAD and marked functional impairment, or those whose symptoms have not responded adequately to low intensity psychological interventions. Discuss the treatment options, side effects, potential interactions and any concerns with the service user and provide the relevant medication information leaflet. SSRIs are the first-line treatments for GAD. NICE recommends sertraline as the drug of choice (off-label) as it has proved clinically effective in the use of mixed anxiety and depressive disorder and it is the most cost-effective drug. If sertraline is ineffective, offer an alternative SSRI (e.g. escitalopram or paroxetine) or an SNRI (venlafaxine or duloxetine), taking into account the following factors: o side-effect profile and potential for drug interactions o the person's prior experience of treatment with individual drugs (particularly adherence, effectiveness, side effects, experience of withdrawal symptoms and personal preference). o risk of a withdrawal syndrome (especially with paroxetine and venlafaxine) o the risk of suicide and likelihood of toxicity in overdose (especially with venlafaxine) If the person cannot tolerate SSRIs or SNRIs, consider offering pregabalin. Use low initial doses of antidepressant and titrate up slowly. Initial worsening of anxiety may be evident. Antidepressants can take several weeks to have an effect. The full anxiolytic effect will develop gradual over 1 week or more. If a drug is effective, it should be continued for at least a year as the likelihood of relapse is high. If there is severe anxiety that is disabling and causing the person significant distress, consider prescribing short-term treatment with a benzodiazepine (for example diazepam). Prescriptions of short duration should be given, with regular review of the patient, and treatment should last no longer than 2 to 4 weeks. For people starting on an antidepressant, initially review after two weeks (one week if aged under 30 years or risk of suicide) Review the effectiveness and side effects of medication every 2 4 weeks during the first 3 months of treatment and every 3 months thereafter. Optimising the dose of medication, switching to an alternative drug, or stopping drug treatment is recommended if there is no improvement of anxiety symptoms after 2 months of treatment. Anxiety Disorders Next Review: Jan 2019 3

If treatment is effective and tolerable, continue for at least 1 year as risk of relapse is high. If there is a partial response to drug treatment, consider offering a high-intensity psychological intervention in addition to drug treatment. Alcohol or substance misuse should be managed first as it may be contributing to the symptoms of GAD. 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). Relevant NICE Guidance NICE Generalised anxiety disorder and panic disorder (with or without agoraphobia) in adults. CG113 (2011). Available from www.nice.org.uk/guidance/cg113. NICE pathways: Generalised anxiety disorder http://pathways.nice.org.uk/pathways/generalised-anxiety-disorder. NICE quality standards [QS53]. Anxiety disorders. February 2014. Available from: http://www.nice.org.uk/guidance/qs53. Anxiety Disorders Next Review: Jan 2019 4

Generalised Anxiety Disorder First Line: Relative Cost Notes Sertraline Not currently licensed for the treatment of GAD (off-label use); Recommended first-line by NICE If successfully treated previously with another antidepressants, re-initiate prior therapy Offer high-intensity psychological intervention and anxiety management techniques Second Line: Relative Cost Notes Alternative SSRI Offer another SSRI not tried first-line if unable to tolerate treatment or no response after 12 weeks at optimal dose. Checking adherence; confirm diagnosis; if partial response consider dose increase Paroxetine Use lower initial doses; high likelihood of discontinuation reactions liquid Escitalopram Consider preference, side effects - including QT effects and previous response liquid Citalopram Off-label use; obtain consent; consider side effects - including QT effects and previous response liquid Fluoxetine Off-label use; obtain consent; consider long half life, preference, side effects and previous response liquid or SNRI Monitor blood pressure Venlafaxine More toxic in overdose than SSRIs; High risk of discontinuation reactions Tablets XL caps/mr tabs Third Line: Relative Cost Notes Duloxetine Monitor blood pressure Brand Pregabalin NICE recommends pregabalin only if SSRIs or SNRIs not tolerated; somnolence and dizziness are common. Risk of dependence and misuse. Costs are significantly greater than those for generic SSRI; Twice daily with single capsule dosing is required when discharging patients to GP. Trazodone Consider after non-response to or poor tolerance of SSRI treatment ; sedating liquid Imipramine Off-label use. Avoid tricyclics if risk of suicide; potential for cardiac and CNS toxicity in overdose Anxiety Disorders Next Review: Jan 2019 5

Generalised Anxiety Disorder Other Agents Relative Cost Notes Benzodiazepines eg Diazepam/Lorazepam Liquids Quetiapine Tabs M/R - Not routinely recommended except as a short-term measure during crisis because of risk of side effects, dependence and misuse. Useful adjuncts in agitated service users. Off-label use - limited evidence of benefits; greater risk of discontinuation due to side effects. Only for use in specialist settings. Branded Buspirone For short-term use only delayed onset of action; greater risk of discontinuation due to side effects; Efficacy is reduced in previous extensive use of benzodiazepines; may be useful where benzodiazepines not used before Propranolol M/R Liquid May be useful for somatic symptoms particularly tachycardia; check contraindications Hydroxyzine Limited effectiveness; use for sedative effect inappropriate. MHRA/CHM advice: Risk of QT-interval prolongation and torsade de pointes Treatment Refractory Generalised Anxiety Disorder General principles Antidepressant combinations Antidepressant + Antipsychotic Antidepressants + other agents, e.g. buspirone, diazepam, pregabalin etc Relative Cost Notes Review current and past treatments and adherence. Increase the dose of the current treatment to the maximum dose; Switch to an alternative evidence-based treatment not previously tried Use a combination of psychological interventions and drug treatments. - Seek consultant advice. Limited evidence and side effects and interactions more likely - Consultant initiation only. Do not use routinely due to limited evidence of effect; Side effects and interactions more likely. Long-term use of antipsychotic should be avoided. - Seek consultant advice. No clear evidence of benefit. Check for contraindications Anxiety Disorders Next Review: Jan 2019 6

Panic Disorder with or without Agoraphobia Psychological therapies, drug treatment and self-help are options for treatment of panic disorder. Pharmacologic treatments may be considered if behavioural or cognitive therapy fails. Before prescribing drug treatment, consider age, previous treatment response, risk of overdose, tolerability, potential interactions with concomitant medications, service user preference and costs. Unless otherwise indicated, an SSRI licensed for panic disorder should be first line treatment. To minimise risk of side effects, treatment should be started at a low dose and the dose increased slowly until a satisfactory therapeutic response is achieved. Long-term treatment and doses at the higher end of the recommended range may be necessary when standard doses are inadequate. There may be an initial exacerbation of anxiety and panic symptoms It can take several weeks before the effects of antidepressants are evident When new medication is started, efficacy and side-effects should be reviewed within 2 weeks of initiation and again at 4, 6 and 12 weeks. Treatment should be reviewed at 8 12 weeks intervals if drug used for more than 12 weeks If there is no improvement after 12 weeks, switch to an alternative antidepressant. Remission of symptoms may take up to 6 months or longer (including 4 6 weeks at the highest comfortably tolerated dose). Medication should be continued for 6 months to 1 year at the optimal dose after acute response to reduce the risk of recurrence before the dose is gradually reduced. Long-term treatment and monitoring may be necessary for some people. Antidepressants for panic disorder should be discontinued over at least 4 weeks Benzodiazepines, sedating antihistamines or antipsychotics should not be prescribed for the treatment of panic disorder. Relevant NICE Guidance NICE Generalised anxiety disorder and panic disorder (with or without agoraphobia) in adults. NICE clinical guideline 113 (2011). Available from www.nice.org.uk/guidance/cg113 NICE Pathways: Panic disorder http://pathways.nice.org.uk/pathways/panic-disorder NICE quality standards [QS53]. Anxiety disorders. February 2014. Available from: http://www.nice.org.uk/guidance/qs5 Anxiety Disorders Next Review: Jan 2019 7

Panic Disorder First Line: Relative Cost Notes SSRI e.g. Sertraline Citalopram Escitalopram Paroxetine Liquid formulations - Offer psychological therapies and encourage self help Consider preference, previous response, side effects and potential interactions Start with low doses then gradually increase to a full dose, as tolerated Citalopram is more cardiotoxic than other SSRIs and can cause QT prolongation at higher doses Paroxetine has a short half life and a high risk of withdrawal symptoms Fluoxetine and fluvoxamine are not licenced for panic disorder; may be tried if previous good response shown. Consider long half life when switching or stopping fluoxetine. GI side effects are common with fluvoxamine; bradycardia and ECG changes have been noted Second Line: Relative Cost Notes Imipramine Not licenced for panic disorder but has shown long-term benefit. Consider when an SSRI is not suitable or there is no improvement after a 12-week course and further medication is appropriate; Clomipramine Not licenced for panic disorder but has shown benefit. Consider when an SSRI is not suitable or there is no improvement after a 12-week course Reboxetine Some benefit but less effective than SSRIs; Risk of hypotension and hypokalaemia Venlafaxine Monitor blood pressure; cardiotoxic in overdose Tablets XL capsules/mr tabs Third Line: Relative Cost Notes Mirtazapine Tabs/orodispersible Liquid MAOIs Moclobemide Phenelzine Propranolol M/R Liquid Benzodiazepines Tablets Liquid Not licenced for panic disorder but has shown some benefit; sedating; risk of weight gain Risk of drug interactions and other dietary restrictions limit use; allow a sufficient washout period. Only consider when unresponsive or intolerant to several treatment options Limited evidence but may reduce somatic effects; check contraindications Benzodiazepines should not be prescribed except for short term use in severe, distressing and disabling panic symptoms Anxiety Disorders Next Review: Jan 2019 8

Panic Disorder Not Recommended: Relative Cost Notes Antihistamines Antipsychotics Benzodiazepines - Sedating antihistamines or antipsychotics should not be prescribed for the treatment of PD Benzodiazepines should not be prescribed except as above due to unfavourable outcomes Treatment Refractory Panic Disorder Strategy Relative Cost Notes Assessment Consider and manage comorbidity e.g. depression Review current and past treatments and adherence Increase the dose of the current treatment to the maximum dose; Use a combination of psychological interventions and drug treatments. However, there is little evidence to support the use of pharmacological and psychological interventions in combination Dose escalation - No clear benefit Switching - Switching to an alternative agent with proven efficacy may be helpful Augmentation - Add a benzodiazepine e.g. diazepam, lorazepam, clonazepam or buspirone or CBT Antidepressant combinations - Seek consultant advice. Side effects and interactions more likely. Anxiety Disorders Next Review: Jan 2019 9

Social Anxiety Disorder (SAD) Initial treatment involves individual cognitive behavioural therapy (CBT) developed specifically to treat social anxiety disorder Pharmacological treatment may be considered if the social anxiety disorder (social phobia) interferes significantly with social and occupational activities and if behavioural or cognitive therapy fails or is declined by the service user. SSRIs (escitalopram or sertraline) are considered to be the drugs of choice for the treatment of social anxiety disorder. If there is only a partial responded to an SSRI (escitalopram or sertraline) after 10 to 12 weeks of treatment, an individual CBT in addition to the SSRI may be considered. If symptoms have not responded to an SSRI or service user cannot tolerate the side effects, an alternative SSRI (e.g. paroxetine, fluvoxamine) or a serotonin noradrenaline reuptake inhibitor (SNRI), e.g. venlafaxine may be offered. And if still no response, a monoamine oxidase inhibitor (e.g. phenelzine or moclobemide) may be tried. Dietary and drug interaction advice should be provided. The tendency of paroxetine and venlafaxine to produce a discontinuation syndrome (which may be reduced by extended-release preparations and the risk of suicide and likelihood of toxicity in overdose should be considered. There may be an initial exacerbation of anxiety and agitation. Arrange regular meetings with service user to monitor for adverse effects. Monitor the risk of suicidal thinking and self-harm regularly. Standard antidepressant starting doses are indicated for social phobia Advise and support service users to engage in graduated exposure to feared or avoided social situations. Treatment should be continued for at least 9 months and possibly longer in some cases. Co-morbidities e.g. depression, alcohol and substance misuse should be appropriately managed. Relevant NICE Guidance NICE. Social anxiety disorder: recognition, assessment and treatment. NICE clinical guidelines CG159 May 2013 Available from https://www.nice.org.uk/guidance/cg159 NICE Pathways: Social anxiety disorder. http://pathways.nice.org.uk/pathways/social-anxietydisorder NICE quality standards [QS53]. Anxiety disorders. February 2014. Available from: http://www.nice.org.uk/guidance/ Anxiety Disorders Next Review: Jan 2019 10

Social Anxiety Disorder (Social Phobia) First Line: Relative Cost Notes SSRI e.g. Escitalopram (liquid) Sertraline () Second Line: Relative Cost Notes Offer psychological interventions - CBT is known to be efficacious for long-term treatment SSRIs considered to be the drugs of choice for the treatment of social anxiety disorder Consider combining SSRI + CBT in those with high risk of relapse Continue treatment for 10-12 weeks Alternative SSRI Offer another SSRI not tried first-line if not response to first line treatment or not tolerated Paroxetine (liquid) () High risk of discontinuation reactions Fluvoxamine Risk of nausea and vomiting higher with fluvoxamine than other SSRIs; Risk of interactions. Unlicensed for the treatment of social anxiety disorder SNRIs Venlafaxine (MR) () Monitor blood pressure. High risk of discontinuation reactions; cardiotoxic in overdose Third Line: Relative Cost Notes MAOIs e.g. Phenelzine Moclobemide Fluoxetine liquid Other agents Relative Cost Notes Consider MAOIs when there is no response or intolerance to previous treatments. Delayed effects Phenelzine has proven efficacy but side effects, interactions and dietary restrictions limit use. Phenelzine is unlicensed for the treatment of social anxiety disorder Moclobemide is licensed for social anxiety disorder and has reduced need for dietary restrictions Evidence-based proven efficacy. NICE acknowledges its efficacy but does not mention it as recommended treatment. Fluoxetine is recommended by BAP as a possible choice among other SSRIs. Fluoxetine is unlicensed for the treatment of social anxiety disorder. Anticonvulsants - Consultants only may consider gabapentin; pregabalin Buspirone Consider adding buspirone after partial response to SSRI Clonazepam - Short term use only for severe anxiety as an augmentation strategy; risk of dependence Propranolol Liquid - May be useful for somatic symptoms such as tachycardia, sweating and tremor in performancerelated anxiety; check contraindications Anxiety Disorders Next Review: Jan 2019 11

Treatment-Refractory Social Anxiety Disorder (Social Phobia) Strategy Relative Cost Notes Dose escalation - Optimise dose although evidence of benefit is unclear Switching - Adding, or switching to, an alternative pharmacological treatment Combination - Use combinations of antidepressants only where there are no contraindications Augmentation - Consider antidepressant + benzodiazepine or buspirone or a psychological intervention e.g. CBT Other - Consider and manage co-morbidities Anxiety Disorders Next Review: Jan 2019 12

Obsessive Compulsive Disorder Psychological interventions (e.g. individual or group CBT) are recommended for mild functional impairment. Drug treatment is appropriate for those with poor response to psychological interventions or with moderate to severe functional impairment. A combination of pharmacological, behavioural, and psychosocial methods appears to have the most successful long-term outcome. Fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram are recommended by NICE guidelines for first-line pharmacological treatment of OCD. Serotonin and noradrenaline re-uptake inhibitors (SNRIs), including venlafaxine should not normally be used to treat obsessive compulsive disorder without comorbidity. Clomipramine may be considered when an adequate trial of at least one SSRI was ineffective, or an SSRI was poorly tolerated, or the patient prefers clomipramine, or there has been a previous good response. Clomipramine is more toxic than SSRIs and should be avoided if possible, in people at significant risk of suicide; only prescribe small amounts if clomipramine is necessary. Blood pressure and an electrocardiogram (ECG) should be checked before prescribing clomipramine for adults at significant risk of cardiovascular disease. Do not prescribe in cases of recent myocardial infarction, arrhythmia (particularly heart block), or hypotension. Doses at the upper end of the indicated dose range and a longer duration of treatment (at least 12 weeks) for an initial response may be necessary. Monitor for response, adverse effects, worsening anxiety, suicidal thoughts, and self harm Most people will not experience substantial improvement until 4 6 weeks after starting medication, and others may show little improvement for up to 12 weeks. If successful, pharmacological treatment should be continued for 1 2 years (at least 12 months) to prevent relapse and allow further improvements before considering a gradual taper off over 1 2 months while monitoring for exacerbation or return of symptoms. Discontinuation of treatment should be carefully considered. Most people with require continued treatment of some form. Gradual withdrawal over several months may be more successful if also receiving psychological/behavioural therapies. Relevant NICE Guidance NICE Obsessive-compulsive disorder: Core interventions in the treatment of obsessive compulsive disorder and body dysmorphic disorder. NICE: clinical guideline 31 (2005). Available from https://www.nice.org.uk/guidance/cg31. NICE Pathways. Obsessive-compulsive disorder and body dysmorphic disorder. http://pathways.nice.org.uk/pathways/obsessive-compulsive-disorder NICE quality standards [QS53]. Anxiety disorders. February 2014. Available from: http://www.nice.org.uk/guidance/ Anxiety Disorders Next Review: Jan 2019 13

Obsessive Compulsive Disorder (OCD) First Line: Relative Cost Notes SSRI Fluoxetine Sertraline Paroxetine Escitalopram Fluvoxamine Citalopram (unlicensed) Liquid formulations - If CBT is not accessible or available, offer drug treatment. Also offer CBT if medication not preferred and service users able to engage with CBT Citalopram and escitalopram cause dose-dependent QT interval prolongation Fluoxetine has a long half life. Paroxetine can cause more weight gain and anticholinergic side effects than are other SSRIs and greater risk of withdrawal symptoms. Fluvoxamine may cause more side effects (e.g., insomnia, nausea, vomiting) and interactions than other SSRIs. Second Line: Relative Cost Notes Alternative SSRI - Offer SSRI not tried first line or escitalopram (NB: costs greater than for generic SSRIs) Liquids - Clomipramine Consider clomipramine when SSRI ineffective or poorly tolerated or when it is the preferred option or where previous good response has been shown. Clomipramine is more likely to induce anticholinergic effects and can cause hypotension and postural dizziness. It can increase levels of liver transaminases and has a potential for seizures and cardiac arrhythmias, particularly at higher doses. Consider ECG and blood pressure monitoring in cardiovascular disease Anxiety Disorders Next Review: Jan 2019 14

Obsessive Compulsive Disorder (OCD) continued Third Line: Relative Cost Notes Combinations e.g. SSRI + clomipramine SSRI + mirtazapine Augmentation e.g. SSRI + antipsychotic SSRI + trazodone SSRI+ lamotrigine SSRI + pregabalin Benzodiazepines e.g. - - - - - Consultant initiation only- monitor carefully risk of additive side effects and toxicity; Off-label use- mirtazapine can also be considered Antipsychotics (risperidone, quetiapine, haloperidol, aripiprazole) can be considered as augmentation strategy where response to SSRI treatment is poor or incomplete May be helpful in alleviating OCD and anxiety as well as sleep disturbances Modest evidence, consider on a individual basis when other strategies have failed Modest evidence, consider on a individual basis when other strategies have failed Benzodiazepines are not routinely recommended due to limited evidence for efficacy. Only consider for short periods for severe anxiety Consider phenelzine when other strategies have failed and the patient shows atypical obsessive symptoms eg asymmetry. Should not normally be used without comorbidity clonazepam; diazepam (liquids ) MAOIs Phenelzine Venlafaxine - Not routinely recommended. More toxic in overdose than SSRIs. High risk of discontinuation reactions. NICE states that SNRIs should not normally be used without comorbidity Treatment-Refractory Obsessive Compulsive Disorder Strategy Relative Cost Notes Dose escalation - Optimise dose higher than licensed doses may be required - off-label use. Monitor for side effects and toxicity. Switching - Switch to another pharmacological treatment or psychological treatment nor previously tried Combination - Use drug combinations where not contraindicated or combine with psychological treatment. Combination of drug treatment with psychological interventions (CBT) may be required. A combination of SSRIs and CBT is superior to monotherapy and can reduce relapse Augmentation (less evidence) - Consultant may consider adding an antipsychotic (e.g. risperidone, aripiprazole) to SSRI or clomipramine - increased risk of side effects; adding lamotrigine, topiramate or buspirone Anxiety Disorders Next Review: Jan 2019 15

Post-Traumatic Stress Disorder Post-traumatic stress disorder (PTSD) develops following a stressful event or situation of an exceptionally threatening or catastrophic nature. A number of PTSD sufferers may recover with watchful waiting or limited interventions. However, without effective treatment, many may develop chronic problems over many years. Drug therapy is largely aimed at managing accompanying symptoms of anxiety or panic disorder or depression or drug/alcohol misuse. Pharmacological treatments should be offered to people who: o express a preference not to engage in trauma-focused psychological treatment o cannot start psychological therapy because of serious ongoing threat of further trauma o have gained little benefit from a course of trauma-focused therapy Drug treatments should also be considered: o in the acute phase of PTSD for the management of sleep disturbance o as an adjunct to psychological treatment in adults where there is significant comorbid depression or severe hyperarousal that impacts on a sufferer s ability to benefit from psychological treatment NICE recommends the use of paroxetine, mirtazapine (unlicensed indication), amitriptyline (unlicensed indication), or phenelzine (unlicensed indication) in people who refuse psychotherapy, where psychotherapy is inappropriate or ineffective, or as adjunctive therapy in significant comorbid depression or severe hyperarousal. Lower initial dose are recommended although higher target doses (within approved limits) may prove necessary for full effect. Treatment periods of 8-12 weeks are needed to assess efficacy If there is a good response, continue treatment for at least 12 months before gradual withdrawal. Effectiveness and tolerability should be assessed regularly throughout treatment. Paroxetine is associated with significant withdrawal (discontinuation) symptoms. Side effects and the need to follow dietary restrictions limit the use of phenelzine and it should generally be reserved for patients who have not responded to, or have proved intolerant of other treatment approaches. Continued use of an antidepressant should be reviewed if the person with PTSD develops marked and/or prolonged akathisia. Where sleep is a major problem for an adult PTSD sufferer, offer advice on sleep hygiene; hypnotic medication may be appropriate for short-term use only but if required in the long-term, use of a suitable sedative antidepressant (e.g. mirtazapine) should be considered to reduce risk of dependence. Psychological therapies should be used for young people with PTSD. Drug treatments must not routinely be prescribed. Relevant NICE Guidance NICE. Post-traumatic stress disorder: the management of PTSD in adults and children in primary- NICE clinical guideline 26 (2005). Available from http://www.nice.org.uk/guidance/cg26 NICE Pathways. Post-traumatic stress disorder. http://pathways.nice.org.uk/pathways/posttraumatic-stress-disorder. NICE quality standards [QS53]. Anxiety disorders. February 2014. Available from: http://www.nice.org.uk/guidance/ Anxiety Disorders Next Review: Jan 2019 16

Post Traumatic Stress Disorder (PTSD) First Line: Relative Cost Notes SSRI e.g. Paroxetine (liquid) Sertraline Mirtazapine Tabs/Orodispersible Liquid () Offer trauma-focused psychological therapies before drug treatment Continue drug treatment for 12 months if response is evident at 12 weeks Paroxetine and sertraline have current licences for PTSD Off-label use; sedation and weight gain likely; blood dyscrasias - monitor Second Line: Relative Cost Notes Alternative SSRI Citalopram If first line SSRI unsuccessful, an suitable alternative SSRI e.g. citalopram or fluoxetine (off-label use) can be tried Fluoxetine Venlafaxine (M/R) () Venlafaxine may be considered as an alternative to SSRIs following non-response - preferred over tricyclics or MAOIs as less adverse effects Amitriptyline or Imipramine Monitor for side effects; potentially cardiotoxic MAOIs i.e. phenelzine Other Treatments Relative Cost Notes Consultant only; Can reduce traumatic recollections and nightmares, and repress flashbacks; MAOI treatment requires careful BP monitoring and advice on drug and food interactions Hypnotics May be appropriate for short-term use only where lack of sleep is a major problem; risk of liquids - dependence Benzodiazepines (liquids ) May be helpful for short-term management of severe anxiety; risk of dependence and misuse Propranolol - Consider for preventing post-traumatic symptoms if there are no contra-indications Liquid Antiepileptic drugs - Carbamazepine, valproate, topiramate limited benefits in some benefits; off-label for specific symptom clusters; e.g. hyper-reactivity, violent behaviour, angry outbursts, avoidance (social withdrawal) and intrusion Anxiety Disorders Next Review: Jan 2019 17

Treatment-Refractory Post Traumatic Stress Disorder Strategy Relative Cost Notes Dose escalation - Consider increasing the dosage within approved limits if tolerated. No clear evidence of benefit. Switching - Consider switching to a different class of antidepressant treatment or using psychological therapy Combination - Seek consultant advice. Use combinations of medication where there are no contraindications Consider adding psychological treatment especially where there is comorbid depression or severe hyperarousal Augmentation - Consider adding a second generation antipsychotic consultant initiation only. e.g. add olanzapine to reduce post-traumatic and depressive symptoms and sleep disturbance OR risperidone in those with coexisting psychotic symptoms or aggression OR as an adjunct to SSRI antidepressants in refractory cases; Antipsychotics may also be considered where paranoia or flashbacks are prominent BAP guidelines also recommend adding prazosin in reducing nightmares and other PSTD symptoms Co-morbidities - Review and manage co-morbidities e.g. sleep disorders, severe depression, anxiety, self harm and substance misuse. Consider treating PTSD first unless depression is so severe that it makes psychological treatment very difficult, in which case treat the depression first. Treat any significant drug or alcohol problem before treating the PTSD Anxiety Disorders Next Review: Jan 2019 18

Appendix 1 Pharmacological Agents For Anxiety Disorders Licensed Indications And Doses Drug (SSRIs) Licensed Indications Dose Recommendations Citalopram Escitalopram Sertraline Panic Disorder (PD) with or without agoraphobia Depressive illness General Anxiety Disorder (GAD) Panic Disorder with or without agoraphobia. Obsessive Compulsive Disorder OCD Social phobia/ Social Anxiety Disorder (SAD) Depressive illness Obsessive Compulsive Disorder (OCD) Post Traumatic Stress Disorder (PTSD) Panic Disorder with or without agoraphobia. Social phobia/ Social Anxiety Disorder (SAD) Depressive illness GAD PD OCD SAD PTSD Initially 10 mg/day for first week, gradually increased in 10mg steps; recommended dose 20-30 mg daily; max 40mg daily and 20mg if over 65yrs Initially 10 mg/day. max 20 mg/day Elderly and hepatic impairment - half the usual dose and lower max. dose Initially 5mg/day increased to 10mg after 7 days, max 20mg od. Elderly and hepatic impairment - half the usually dose and lower max. dose of 10mg Initially 25mg/day increased after one week to 50mg/day May be further increased in steps of 50mg at intervals of at least one week, max 200mg/day. Initially 10 mg/day. max 20 mg/day Elderly and hepatic impairment - half the usually dose and lower max. dose hepatic impairment half adult dose Initially 50mg/day Dose may be increased by 50mg increments at intervals of at least one week, max 200mg/day Initially 10mg/day adjusted after 2-4 weeks; Usual dose 5-20mg.max 20mg Elderly - efficacy not studied hepatic impairment half adult dose Initially 25mg/day increased after one week to 50mg/day May be further increased in steps of 50mg at intervals of at least one week, max 200mg/day. Initially 25mg/day increased after one week to 50mg/day May be further increased in steps of 50mg at intervals of at least one week, max 200mg/day Anxiety Disorders Next Review: Jan 2019 19

Appendix 1 continued. Pharmacological agents for anxiety disorders licensed indications and doses Drug (SSRIs) Fluvoxamine Fluoxetine Licensed Indications Obsessive Compulsive Disorder (OCD) Depressive illness Obsessive Compulsive Disorder (OCD) Depressive illness Bulimia nervosa Dose Recommendations GAD PD OCD SAD PTSD - - Initially 50 in the - evening. May be gradually increased to a maximum of 300 mg. Usual dose 100-300mg. Total daily dose of more than 150mg is given in 2-3 divided doses. - Initially 10mg daily 20mg /day, max - increased to 20mg/day usually 40mg od, after a week; further but 60mg od has increases to 60 mg daily been used. Up to 80 (unlicensed use) mg daily has been used, sometimes divided into 2 doses. Anxiety Disorders Next Review: Jan 2019 20

Pharmacological agents for anxiety disorders licensed indications and doses Drug (SSRIs/SNRIs) Paroxetine Duloxetine Venlafaxine Licensed Indications General Anxiety Disorder (GAD) Panic Disorder (PD) Obsessive Compulsive Disorder (OCD) Social Anxiety Disorder (SAD) Post Traumatic Stress Disorder (PTSD) Depressive illness General Anxiety Disorder (GAD) Depressive illness General Anxiety Disorder (GAD) Panic Disorder with or without agoraphobia. Social Anxiety Disorder (SAD) Depressive illness Dose Recommendations GAD PD OCD SAD PTSD Initially Initially 10mg daily; increased Initially 20mg daily; Initially 20mg/day, Initially 20mg/day, weekly in 10mg steps to a usual increased weekly in (limited efficacy at 20mg/day, (limited efficacy maintenance dose of 40 mg 10mg increments to higher doses) (limited efficacy at higher doses) daily; (limited efficacy at higher a usual further increases in at higher doses) further increases doses but some may require up maintenance dose increments of 10 further increases in increments of to 60mg daily; max 60mg of 40 mg daily; mg at intervals of in increments of 10 mg at intervals (40mg od in elderly) (limited efficacy at at least one week 10 mg at intervals of at least one higher doses but to a maximum of of at least one week to a some may require 50mg/day (40mg week to a maximum of up to 60mg daily; od in elderly) maximum of 50mg/day (40mg max 60mg 50mg/day (40mg od in elderly) (40mg od in elderly) od in elderly) Initially 30mg daily, increased to 60mg once daily; may be increased to 90-120mg/daily Initially 75mg/day; may be increased to max 225mg/day. Dosage increases can be made at intervals of 2 weeks or more. Initially 37.5 mg/day for 7 days increased to 75 mg/day. Further increases can be made in 75mg steps after at least 2 weeks to max 225mg/day. Initially 75mg/day; may be increased to max 225mg/day. Dosage increases can be made at intervals of 2 weeks or more. Anxiety Disorders Next Review: Jan 2019 21

Pharmacological Agents for Anxiety Disorders Licensed Indications and Doses Drug Amitriptyline Licensed Indications Depressive illness Dose Recommendations GAD PD OCD SAD PTSD initially 75 mg (elderly 30 75mg) daily in divided doses or as a single dose at bedtime increased gradually as necessary to 150 200mg Clomipramine Phobic and obsessional states Depressive illness Initially 25 mg daily (elderly 10 mg daily) increased over 2 weeks to 100 150 mg daily; max. 250 mg daily Initially 25 mg daily (elderly 10 mg daily) increased over 2 weeks to 100 150 mg daily; max. 250 mg daily Initially 25 mg daily (elderly 10 mg daily) increased over 2 weeks to 100 150 mg daily; max. 250 mg daily Imipramine Depressive illness Initially 10mg/day may be increased gradually to 75 to 150mg/day; doses of 200mg daily may be necessary Elderly, lower doses - 30 50 mg daily (Unlicenced) Trazodone Depression including with anxiety Anxiety, 75 mg daily, increasing as necessary to 300 mg daily Anxiety Disorders Next Review: Jan 2019 22

Pharmacological Agents for Anxiety Disorders Licensed Indications and Doses Drug MAOIs Moclobemide Licenced Indications Social anxiety disorder (SAD) Depressive illness Dose Recommendations GAD PD OCD SAD PTSD Social anxiety disorder, initially 300 mg daily increased on fourth day to 600 mg daily in 2 divided doses, continued for 8 12 weeks to assess efficacy Phenelzine Mixed anxiety and depression and phobic or hypochondriacal features (Depression characterised as 'atypical', 'non endogenous', 'neurotic' or where treatment with other antidepressants has failed) 15mg three times daily; if no response after 2 weeks, increase to 15 mg four times daily; severely depressed patients in hospital may be given up to 30mg three times daily; then reduced gradually to lowest possible maintenance dose (15 mg on alternate days may be adequate) 15mg three times daily; if no response after 2 weeks, increase to 15 mg four times daily; severely depressed patients in hospital may be given up to 30mg three times daily; then reduced gradually to lowest possible maintenance dose (15 mg on alternate days may be adequate) 15mg three times daily; if no response after 2 weeks, increase to 15 mg four times daily; severely depressed patients in hospital may be given up to 30mg three times daily; then reduced gradually to lowest possible maintenance dose (15 mg on alternate days may be adequate) Anxiety Disorders Next Review: Jan 2019 23

Pharmacological Agents for Anxiety Disorders Licensed Indications and Doses Drug Other Pregabalin Benzodiazepines Diazepam Lorazepam Clonazepam Licensed Indications Generalised Anxiety Disorder (GAD) in adults Short term use in severe anxiety Short term use in severe anxiety Not licenced for anxiety Dose Recommendations GAD PD OCD SAD PTSD Initially 150mg/day; this may be increased at weekly intervals in steps of 150 mg, to a maximum of 600 mg daily 1-4mg daily in divided doses 2mg 3 times daily, increased if necessary to 15-30mg daily Initial oral dose of 250 micrograms twice daily. This may be increased after 3 days to a total of 1 mg daily Anxiety Disorders Next Review: Jan 2019 24

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