Medication for Anxiety and Depression PJ Cowen Department of Psychiatry, University of Oxford
Topics Medication for anxiety disorders Medication for first line depression treatment Medication for resistant depression Recent studies with ketamine
Clinical Approach to Diagnosis Baldwin et al, 2014
EU Community Studies of Anxiety Disorders Diagnosis 12 month Pharmacological prevalence (%) Treatment Specific phobia 6.4 N/A PTSD 2.9 SSRI Panic (± agoraphobia) 1.8 SSRI Agoraphobia (- panic) 2.0 SSRI Social Phobia 2.3 SSRI GAD 2.5 SSRI OCD 0.7 SSRI
SSRIs and SNRIs in Anxiety Disorders SSRI Paroxetine Fluoxetine Sertraline Citalopram Escitalopram Venlafaxine Duloxetine Licensed Indications (additional to major depression) GAD, Panic, SAD, OCD, PTSD OCD Panic, SAD, OCD, PTSD Panic GAD, Panic, SAD, OCD GAD, Panic, SAD GAD
Pregabalin in GAD Mode of action uncertain. Probably via blockade of a subunit of calcium channels Side effects profile different to SSRI. Somnolence dizziness, increased appetite. Loss of visual acuity reported rarely. Withdrawal symptoms can occur (insomnia, anxiety) Daily dose 150-600mg (2 or 3 x daily). No clear dose response Misuse potential Can be combined with antidepressants
NICE Guidelines for Anxiety Stepped Care Approach Psychological treatments preferred Generally recommend SSRIs if drug therapy needed. SNRI second line. Pregabalin third line (GAD). Benzodiazepines- maximum 2-4 weeks Continuation treatment generally indicated
Depression-threshold for prescribing (NICE) Antidepressants not recommended for mild depression (PHQ 9 < 15)- unless chronic symptoms or previous history of more severe depression PHQ9 15-19 Antidepressants or psychotherapy PHQ9 > 19 Antidepressants and psychotherapy Normally choose an SSRI in generic form (but not, if patient taking: triptans, NSAIDs, warfarin, heparin, aspirin)- Consider mirtazapine or use SSRI with gastroprotective medicine (except triptan).
Network Meta-Analysis of Antidepressant Efficacy in Major Depression Cipriani et al, 2018
Efficacy and Tolerability of Antidepressants in Major Depression Cipriani et al, 2018
Early Pharmacological Approaches to TRD (NICE) 1. Consider raising dose (allows time for natural recovery to start and to carry out further assessments) 2. Switch (initially another SSRI, or a better tolerated new generation antidepressant) 3. An antidepressant of a different pharmacological class that may be less well tolerated (eg a TCA (but not dosulepin),venlafaxine, or an MAOI)
Different Class vs SSRIs Switch in SSRI- Resistant patients Papakostos et al 2007
Further Management (NICE Guidelines) 1. Antidepressant combination (eg mirtazapine with SSRI or SNRI; in US bupropion plus SSRI popular) 2. Lithium augmentation 3. Atypical antipsychotic augmentation
Mirtazapine Addition to Ineffective SSRI/SNRI Treatment 480 depressed patients on SSRI/SNRI at least six weeks Randomised to mirtazapine addition (up to 30mg) or placebo. Primary outcome BDI at 12 weeks Adjusted difference in scores -1.83 (-3.92-0.27; p= 0.087) Conclusion- No convincing evidence of clinical benefit
Meta-analysis of atypical antipsychotic augmentation of SSRI treatment Agent and study Olanzapine studies Shelton et al Shelton et al Corya et al Thase et al I Thase et al II Subtotal Risperidone studies Mahmoud et al Keitner et al Reeves et al Subtotal Quetiapine studies Khullar et al Mattingly et al McIntyre et al Earley et al El-Khalili et al Subtotal Aripiprazole studies Berman et al Berman et al Marcus et al Subtotal Treatment, n 6 / 10 25 / 146 69 / 230 24 / 102 30 / 98 586 26 / 137 32 / 62 4 / 12 211 3 / 8 11 / 24 9 / 29 110 / 327 112 / 289 677 47 / 181 64 / 174 47 / 185 540 Control, n 2 / 10 18 / 142 10 / 56 18 / 104 16 / 102 414 12 / 131 8 / 33 2 / 11 175 0 / 7 2 / 13 5 / 29 38 / 160 35 / 143 352 27 / 172 32 / 169 28 / 184 525 Odds ratio (fixed) (95% CI) Odds ratio (fixed) (95% CI) 6.00 (0.81, 44.35) 1.42 (0.74, 2.74) 1.97 (0.94, 4.13) 1.47 (0.74, 2.91) 2.37 (1.20, 4.70) 1.83 (1.30, 2.56) 2.32 (1.12, 4.83) 3.33 (1.30, 8.53) 2.25 (0.32, 15.76) 2.63 (1.51, 4.57) 9.55 (0.40, 225.19) 4.65 (0.84, 25.66) 2.16 (0.62, 7.49) 1.63 (1.06, 2.50) 1.95 (1.25, 3.06) 1.89 (1.41, 2.54) 1.88 (1.11, 3.19) 2.49 (1.52, 4.08) 1.90 (1.13, 3.19) 2.09 (1.55, 2.81) Total 2014 1466 2.00 (1.69, 2.37) 0.1 0.2 0.5 1 2 5 10 Favours control Favours treatment SSRI, selective serotonin reuptake inhibitor; CI, confidence interval Nelson JC, Papakostas GI. Am J Psychiatry 2009;166:980-91
Meta-Analysis of Atypical Antipsychotic augmentation of SSRI Treatment (ii) Response rate 44.2% vs 29.9% Remission rate 30.7% vs 17.2% For Response NNT= 9 For Remission NNT= 9 Discontinuation (adverse effects) NNH= 17 (Papakostas and Nelson, 2009)
Network Meta-analysis of Augmentation Treatments for Resistant Depression (n= 6,700) * * * * Zhou et al, 2015
LQD Study Funded by NIHR Multi-centre-pragmatic study of lithium versus quetiapine as add-on therapy in patients with TRD (persisting depression despite having tried two or more antidepressants in current episode). 276 patients randomised openly to 12 months treatment Referral: Oxfordhealth.trdclinic@nhs.net
Ketamine as an Antidepressant Ketamine is an antagonist at glutamate NMDA receptors Used as general anaesthetic At sub-anaesthetic doses, intravenous ketamine can provide some temporary relief from depression in resistant depression (bipolar and unipolar)
Ketamine produces a rapid alleviation of depression in TRD Zarate et al 2006
Meta-analysis of Ketamine Remission in TRD McGirr et al, 2015
Subsequent Experience with Ketamine Transient antidepressant effect (1-7 days) confirmed in numerous controlled studies (NNT for response 3-5). Response not generally maintained with available glutamatergic agents (memantine, riluzole). Other NMDA and glutamate receptor antagonists developed by Industry not consistently effective in trials Intranasal s-ketamine may be effective and more useful for longer-term maintenance. Worries about longer-term adverse effects remain
Conclusions For anxiety, psychological treatment preferred. SSRIs first line if drug treatment needed. SSRIs continue to be first line medication for the treatment of depression. Escitalopram (now generic) offers the best balance of acceptability and risk. Mirtazapine is non-ssri alternative. Switching within or between class is a reasonable option if a patient with depression is insufficiently helped by an initial SSRI Augmentation with low dose atypical antipsychotic drugs is probably effective but the adverse effect burden is troublesome. Utility vs lithium needs exploring Ketamine might provide symptomatic relief for patients who have persistent depressive symptoms despite multiple trials of psychological and pharmacological treatment