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 prevalence (%)

Pharmacological 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 Licensed Indications (additional to major depression)

Paroxetine GAD, Panic, SAD, OCD, PTSD

Fluoxetine OCD

Sertraline Panic, SAD, OCD, PTSD

Citalopram Panic

Escitalopram GAD, Panic, SAD, OCD

Venlafaxine GAD, Panic, SAD

Duloxetine 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

Nelson JC, Papakostas GI. Am J Psychiatry 2009;166:980-91

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 Total

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 2014

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 1466

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) 2.00 (1.69, 2.37)

Odds ratio (fixed) (95% CI)

0.1 10 Favours control Favours treatment

0.2 0.5 1 2 5

SSRI, selective serotonin reuptake inhibitor; CI, confidence interval

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

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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