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DTB CME/CPD* Management of adults with PTSD part II: drugs and other interventions

Exposure to traumatic events is common, and many people experience some symptoms following such exposure. In most people, these symptoms subside within a few weeks, but for others, post-traumatic stress disorder (PTSD) develops and may be long-lasting. Part I of this article (DTB 2014; 52: 33–6) discussed the recognition of PTSD and evidence for trauma- focused psychological treatment (generally considered to be first-line treatment). Here in part II of the article, we discuss other possible second-line options: pharmacological treatments and other therapies.

Pharmacological treatment of PTSD • tricyclic antidepressants (TCAs e.g. amitriptyline), • monoamine oxidase (MAO) inhibitors (e.g. phenelzine), • Pharmacological therapies that have been tried for PTSD include: • alpha-blockers (e.g. prazosin), • selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine, sertraline, fluoxetine), • second-generation (atypical) antipsychotics (e.g. risperidone), • serotonin and norepinephrine reuptake inhibitors (SNRIs e.g. venlafaxine), • anticonvulsants (e.g. topiramate), • other second-generation antidepressants (e.g. bupropion, mirtazapine, • benzodiazepines (e.g. alprazolam) and trazodone), • other drugs (e.g. cycloserine).1 The British National Formulary (BNF) suggests that PTSD can be treated with SSRIs (e.g. paroxetine or sertraline).2 The National Institute for Health and Care * DTB CME/CPD A CME/CPD module based on this article is available for completion online via BMJ Excellence (NICE) evidence update of December 2013 notes that fluoxetine, Learning (learning.bmj.com) by subscribers to the online version of DTB. If prompted, venlafaxine, mirtazapine, amitriptyline, phenelzine, risperidone, topiramate, and subscribers must sign into DTB with their username and password. All users must cycloserine do not have UK marketing authorisation for use in PTSD; informed also complete a one-time registration on BMJ Learning and subsequently log in (with consent should be obtained and documented for a drug used off-label.3 Currently, a BMJ Learning username and password) on every visit. The answers to the multiple only paroxetine and sertraline are approved by the US Food and Drug choice questions will be freely available on dtb.bmj.com on publication of the next 1,4,5 issue of DTB. Administration and licensed in Europe for treatment of patients with PTSD. The drugs with UK marketing authorisation for treatment of PTSD are shown in Box 1.

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Box 1: Drugs with UK marketing authorisation Box 2: Outcome rating scales for treatment of PTSD Clinician-Administered PTSD Scale (CAPS): Thirty-item structured Paroxetine—recommended dose is 20mg daily. If, after some weeks interview administered by a trained professional. Corresponds to on the recommended dose, insufficient response is seen, some the DSM-5 criteria for PTSD symptoms, impact on functioning, patients may benefit from having their dose increased gradually in response validity, lifetime diagnosis, and overall PTSD severity. 10mg steps up to a maximum of 50mg/day. Long-term use should be Range: 0–136 regularly evaluated.4 0–19: asymptomatic/few symptoms Sertraline—therapy should be initiated at 25mg daily. After 1 week, the dose should be increased to 50mg once daily. Patients not responding 20–39: mild PTSD/sub-threshold to a 50mg dose may benefit from dose increases. Dose changes should 40–59: moderate PTSD/threshold be made in steps of 50mg at intervals of at least 1 week, up to a maximum of 200mg/day. Changes in dose should not be made more 60–79: severe frequently than once per week given the 24-hour elimination half-life ≥80: extreme PTSD1,7,8 of sertraline.5 Hamilton Depression Rating Scale (HAMD): Seventeen-item clinician administered scale used to measure the severity of depressive In a number of studies of pharmacological interventions for PTSD, symptoms. substantial reduction in symptoms occured in the placebo treatment arms. Guidelines have suggested that although there is little difference between Range: 0–54 active therapy and placebo arms, drug therapy may still have a value in the 0–7: in the normal range (or in clinical remission) management of PTSD.6 ≥20: at least moderate severity1,9,10 Antidepressants: SSRIs and SNRIs Impact of the Event Scale-Revised (IES-R): Twenty-two-item self-report measure assessing current subjective distress for any In a systematic review, compared with placebo, paroxetine reduced specific life event. Each item rated on a scale of 0 (not at all), 1 (a little PTSD symptoms more (weighted mean difference [WMD] in Clinician- bit), 2 (moderately), 3 (quite a bit) or 4 (extremely) according to the Administered PTSD Scale [CAPS; see Box 2] –12.6, 95% CI –15.7 to –9.5, 2 past 7 days. RCTs, n=886, effect size Cohen’s d –0.49 [small to medium]) and depression symptoms more (Montgomery Åsberg Depression Rating Scale Range: 0–8811 [MADRS; see Box 2] WMD –5.7, 95% CI –7.1 to –4.3, 2 RCTs, n=886); 12.9% more people achieved remission (p=0.008, 2 RCTs, n=346, number- Montgomery Åsberg Depression Rating Scale (MADRS): Ten-item needed-to-treat [NNT]=8).1 clinician rated measure that assesses the severity of depression. The NICE 2005 analysis of sertraline (including data from six published Range: 0–60 trials and two unpublished industry trials) did not demonstrate clinically 0–6: normal/symptom absent important or statistically significant effects.21 In the later systematic review, compared with placebo, sertraline reduced PTSD symptoms (CAPS WMD 7–19: mild depression = –4.9, 95% CI –7.4 to –2.4, 7 RCTs, n 1,085, effect size Cohen’s d –0.25 [small 20–34: moderate depression to medium]) but did not significantly reduce depression symptoms (Hamilton Depression Rating Scale [HAMD; see Box 2] WMD –0.77, 95% CI >34: severe depression1,12 –2.1 to 0.55, 5 RCTs, n=1,010) or increase remission rates (24.3% vs. 19.6%, p=NS, 1 RCT, n=352).1 Posttraumatic Diagnostic Scale (PDS): Forty-nine-item self-report measure including the Posttraumatic Symptom Scale-Self Report (PSS-SR) Compared with placebo, fluoxetine reduced PTSD symptoms (CAPS WMD which has the following properties: –6.97, 95% CI –10.4 to –3.5, 4 RCTs, n=835, effect size Cohen’s d –0.31 [small to medium]) and depression symptoms (MADRS WMD –2.4, 95% CI –3.7 to 17 PTSD symptoms, each rated for severity from 0 (not at all or only one –1.1, 2 RCTs, n=712) but did not increase remission rates (13% vs. 10%, p=0.72, time) to 3 (5 or more times a week/almost always). 1 1 RCT, n=52). Range: 0–51 A second systematic review reported that paroxetine was more effective than >13 indicates likelihood of PTSD13–15 sertraline and fluoxetine in reducing symptom severity assessed using CAPS 22 score (p=0.001 and p=0.08, respectively). Short PTSD Rating Interview (SPRINT): Eight-item self-report measure In a systematic review, compared with placebo, venlafaxine ER reduced PTSD assessing the core symptoms of PTSD (intrusion, avoidance, numbing, symptoms (CAPS WMD –7.2, 95% CI –11.0 to –3.3, 2 RCTs, n=687) and arousal), somatic malaise, stress vulnerability, and role and social depression symptoms (HAMD WMD –2.08, 95% CI –3.12 to –1.04, 2 RCTs, n=687) functional impairment. Symptoms are rated on five point scales from and increased remission (risk difference 12%, 95% CI 5% to 19%, 2 RCTs, 0 (not at all) to 4 (very much). 1 n=687, NNT=9). Range: 0–32 The systematic review found that the evidence was insufficient to determine >6: symptomatic PTSD16,17 the efficacy of citalopram.1 The Committee on Safety of Medicines has reported that, as with other Structured Interview for PTSD (SIP or SI-PTSD): Seventeen items antidepressants, SSRIs and related antidepressants, especially paroxetine assessing PTSD symptoms and survival and behavioural guilt. For each and venlafaxine, are associated with withdrawal reactions, which may be item, the interviewer assigns a severity rating that reflects frequency severe. The most commonly experienced withdrawal reactions are and intensity. Items are scored on a scale from 0 (not at all) to 4 dizziness, numbness and tingling, gastrointestinal disturbances (extremely severe on a daily basis or produces so much distress that (particularly nausea and vomiting), headache, sweating, anxiety and patient cannot work or function socially). A symptom is counted as 18–20 sleep disturbances; these are less severe when the dose is tapered positive if it is rated ≥2 (moderate). gradually over a period of several weeks.23

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Alpha blockers A systematic review found that internet-based cognitive behavioural therapy In a systematic review, compared with placebo, prazosin did not reduce PTSD (CBT) or internet-based trauma-focused writing sessions improved PTSD symptoms (CAPS WMD –8.9 95% CI –22.1 to 4.3, 2 RCTs, n=50).1 symptoms more than waiting list controls (large effect size: Cohen’s d 1.01, 95% CI 0.76 to 1.26, 5 RCTs, n=398).37 Second-generation (atypical) antipsychotics Combined pharmacological and In a systematic review, compared with placebo, risperidone had little or no psychological therapies clinically significant benefit for reduction of PTSD symptoms (CAPS WMD –4.60, 95% CI –9.0 to –0.2, 4 RCTs, n=419) and the effect on depression symptoms A systematic review included four studies that combined SSRIs with either 38 was not statistically significant (HAMD –3.7 vs. –1.4, p>0.05, 1 RCT, n=65).1 prolonged exposure or cognitive behavioural therapy. Only two trials Evidence from two small trials (total n=34) was insufficient to determine reported a PTSD symptom score and these data could not be combined as one whether olanzapine is efficacious for improving PTSD symptoms, inducing compared the combination with psychological therapy only and the other compared the combination with pharmacotherapy only.38 There was no strong remission or for improving other outcomes for adults with PTSD.1 evidence to show if there were differences between the groups receiving combined interventions compared with psychological therapy (Short PTSD Anticonvulsants Rating Interview [SPRINT; see Box 2] mean difference 2.44, 95% CI –2.87 to In a systematic review, two small trials (<40 patients in each) used topiramate 7.35, 1 RCT, n=65) or pharmacotherapy (Structured Interview for PTSD [SIP; see 38 as monotherapy, and showed no significant difference between the groups on Box 2] mean difference –4.70, 95% CI –10.84 to 1.44, 1 RCT, n=25). PTSD symptom severity.24,25 A more recent RCT found that paroxetine plus exposure therapy improved One RCT (n=232) found no difference between tiagabine and placebo on PTSD PTSD symptoms more than placebo plus exposure therapy (CAPS PTSD or depression symptoms or disability (reduction in CAPS score 30.7 [25.1] vs. symptoms week 5: 40.7 [28.4] vs. 49.0 [23.9], p=0.01; week 10: 21.5 [19.9] vs. 39 30.2 [26.3], p=0.85).26 35.6 [31.3], p<0.001). One RCT (n=82) found no difference between valproate sodium and placebo for PTSD symptoms, anxiety or depression (e.g. CAPS PTSD symptoms at end of treatment at week 8: 60.1 [24.1] vs. 60.8 [26.6]).27 Acupuncture A systematic review of acupuncture for the treatment of PTSD found four RCTs.40 One high-quality RCT (n=84) reported that acupuncture was superior Other drugs to waiting list control for PTSD symptoms (posttraumatic symptom scale-self A systematic review concluded that evidence was insufficient to determine report (PSS-SR; see Box 2) effect size –0.98, p=0.001) and similar to CBT in efficacy for other second-generation antidepressants (bupropion, mirtazapine, terms of effect sizes (PSS-SR CBT effect size –0.85, p=0.004 vs. waiting list).40 1 trazodone), TCAs or benzodiazepines. Another systematic review identified One RCT (n=138) found no difference between electroacupuncture and an four trials of benzodiazepines which all found no difference compared with oral SSRI (mean difference in CAPS PTSD symptoms –0.13, 95% CI –0.47 to 28 placebo or usual care. 0.20).40 One RCT (n=91) found that acupoint stimulation plus CBT was more Two very small RCTs have investigated 3,4-methylenedioxymethamphetamine effective than CBT alone (mean difference in Impact of the Event Scale- (MDMA)–assisted psychotherapy for chronic, treatment-resistant PTSD Revised [IES-R] PTSD symptoms –1.56, 95% CI –2.08 to –1.04).40 A meta- (refractory to both psychotherapy and drug treatment).29,30 One study (n=20) analysis of two RCTs (n=230) found that acupuncture plus moxibustion reported a clinical response (>30% reduction in CAPS PTSD symptom severity) reduced PTSD symptoms more than SSRI (CAPS mean difference –3.19, 95% of 83% in the MDMA group compared with 25% in the placebo group (p value CI –3.93 to –2.46).40 However, the authors noted that there was no RCT in this not stated), with no drug-related serious adverse events.29 Most subjects review with a sham acupuncture control.40 They stated that the results of maintained statistically and clinically significant gains in symptom relief at this systematic review and meta-analysis suggest that evidence of the follow-up (17–74 months after treatment) although two relapsed.31 The other effectiveness of acupuncture for PTSD is “encouraging but not cogent”, study (n=12) found statistically significant reductions in self-assessed PTSD because only two RCTs were included in meta-analysis, and the trials were symptoms compared with placebo (Posttraumatic Diagnostic Scale; see Box 2; of medium- to low-quality.40 change in score, MDMA –8.6 [SD 13.0] vs. 7.3 [SD 6.2], p=0.014) but not clinician-assessed PTSD symptoms (CAPS change in score, MDMA –15.6 [SD 18.1] vs. –3.2 [SD 15.3], p=0.066).30 What do guidelines say? One RCT (n=67) found no significant difference between cycloserine and The NICE guidance from 2005 recommended that: placebo to enhance exposure therapy (remission post-treatment 11/33 [33.3%] vs. 9/34 [26.5%], p=0.24; follow-up: 15/33 [45.5%] vs. 7/34 [20.6%], p=0.11).32 • Drug treatments for PTSD should not be used as a routine first-line treatment for adults (in general use or by specialist mental health professionals) in preference to a trauma-focused psychological therapy. Self-help interventions • Drug treatments (e.g. paroxetine) should be considered for the treatment of An RCT (n=142 people attending A&E after a road traffic accident, occupational PTSD in adults who express a preference not to engage in trauma-focused injury or assault) found no difference between those who received or did not psychological treatment. receive a self-help booklet on PTSD symptoms (Posttraumatic Diagnostic Scale • Where sleep is a major problem for an adult PTSD sufferer, hypnotic post-intervention: 8.83 [10.93] vs. 9.26 [12.43]; follow-up: 8.33 [10.91] vs. 7.80 medication may be appropriate for short-term use but, if longer-term drug [10.61], p=0.12).33 treatment is required, consideration should also be given to the use of suitable antidepressants at an early stage in order to reduce the later risk of An RCT (n=120 people with acute stress disorder) found no difference between dependence. those who received or did not receive a self-help booklet on PDS score (post-intervention: 18.20 [12.17] vs. 18.45 [11.42], p=0.40; 6-month follow-up: • Drug treatments (e.g. paroxetine for general use and amitriptyline for 14.78 [11.92] vs. 14.71 [12.13], p>0.46).34 initiation only by mental health specialists) for PTSD should be considered as an adjunct to psychological treatment in adults when there is significant A systematic review found one RCT comparing a self-help booklet with comorbid depression or severe hyperarousal that significantly impacts on a cognitive therapy or repeated assessments.35,36 Cognitive therapy reduced sufferer’s ability to benefit from psychological treatment. traumatic stress symptoms more than the self-help booklet (PDS SMD 2.00, 95% CI 1.33 to 2.67, n=53); the booklet was no different from repeated • When an adult sufferer with PTSD has responded to drug treatment, it assessments (PDS SMD –0.46, 95% CI –1.01 to 0.09, n=52).35,36 should be continued for at least 12 months before gradual withdrawal.41

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The NICE evidence update of December 2013 notes that, overall, evidence on • adding an adjunctive medication (e.g. risperidone); pharmacological treatment of PTSD remains limited.3 • re-considering the potential for psychological intervention.6 American guidelines from 2004 stated that SSRIs (first-line) and other When an adult sufferer with PTSD has responded to drug treatment, it should antidepressants represent reasonable clinical interventions that are supported be continued for at least 12 months before gradual withdrawal.6 by limited findings in acute stress disorder (ASD) or PTSD.42 Second generation antipsychotics (e.g. risperidone) or anticonvulsants (e.g. topiramate) may be In the context of comorbid PTSD and depression, health practitioners may helpful, but benzodiazepines could not be recommended as monotherapy consider treating the PTSD first, as depression will often improve with in PTSD.42 treatment of PTSD.6 Where the severity of comorbid depression precludes effective engagement in therapy and/or is associated with high-risk Australian guidelines state that evidence suggests that larger clinical effects suicidality, health practitioners are advised to manage the suicide risk and are likely to be obtained from trauma-focused psychological treatment than treat the depression prior to treating the PTSD.6 In the context of PTSD and from pharmacological treatment for most people with PTSD.6 Drugs should not substance use disorders, practitioners should consider integrated be preferentially used as routine first-line treatment for PTSD over trauma- treatment of both conditions.6 Where the decision is made to treat focussed CBT or eye movement desensitisation and reprocessing (EMDR).6 substance use disorders first, clinicians should be aware that PTSD Where drugs are considered, SSRIs should be the first choice.6 SSRI symptoms may worsen due to acute substance withdrawal or loss of antidepressants should be considered when the patient: substance use as a coping mechanism; treatment should include • is unwilling to engage in trauma-focussed psychological treatment; information on PTSD and strategies to deal with PTSD symptoms as the 6 • has a comorbid condition or associated symptoms (e.g. severe depression person controls their substance abuse. and high levels of dissociation) where SSRIs are indicated; • is not sufficiently stable to commence trauma-focussed psychological Which therapies can be used in treatment (e.g. severe ongoing life stress such as domestic violence); primary care? • has not gained significant benefit from trauma-focussed psychological treatment.6 People with PTSD should be assessed and treated by competent individuals, and in many cases this may require referral to a specialist; Where a decision has been made to commence pharmacotherapy, the specialist assessment and treatment with CBT, EMDR or other therapies, person’s mental state should be regularly monitored with a view to plus management of psychological/psychiatric comorbidites requires commencing adjunctive psychological treatment if/when appropriate. In the specialist training.6,41 interim, supportive psychotherapy with a substantial psychoeducational component should be offered.6 Drug therapy may be used in primary care (e.g. where there is comorbid depression), although it is not recommended as a first line option.6,41 Where symptoms have not responded adequately to pharmacotherapy, Drug therapy requires close follow up, dose titration and care in consideration should be given to: eventual withdrawal.6,23 • increasing the dosage within approved limits; Self-help and web-based treatments may be used in conjunction with • switching to an alternative antidepressant medication; other therapies.

Conclusion The key psychological treatments for PTSD recommended in guidelines are trauma-focused cognitive behavioural therapy (CBT) and eye movement desensitisation and reprocessing (EMDR). These treatments are similarly effective (number-needed-to-treat [NNT] of 2 or 3 across different interventions), with EMDR reducing depressive symptoms more than CBT. Pharmacological therapies should not be used first-line, but may be considered second-line or as adjunctive therapy (e.g. where there is comorbid depression). The strongest evidence is for paroxetine; the effect size for monotherapy is small to moderate with an NNT of 8. People with PTSD often have mental health comorbidities (e.g. depression, anxiety, substance misuse, phobia) for which drug therapy may be effective.

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Cover illustration: Constipated colon Credit: Science Photo Library

48 | DTB | Vol 52 | No 4 | April 2014 dtb.bmj.com