Depression Pharmacological Treatments

Dr Rebecca Jacob Consultant Psychiatrist Fulbourn Hospital Cambridge

Depressive disorder: An increasing cause of disability worldwide

Rank 1 2 3 4 5 1990 Lower respiratory infections Diarrhoeal diseases Perinatal conditions Unipolar major depression Ischaemic heart disease 2020 (estimated) Ischaemic heart disease Unipolar major depression Road traffic accidents Cerebrovascular disease Chronic obstructive pulmonary disease Murray CJ, Lopez AD. Science 1996;274:740–3

Epidemiology of depression

Place Manchester (UK) 1 Groningen (Neth) 1 Paris (France) 1 Mainz (Germany) 1 Prevalence (% Pts) 16.9

15.9

13.7

11.2

• Almost twice as common in women than men 2 • Up to 30% of primary care patients have depressive symptoms and 6–10% satisfy criteria for major depressive disorder (MDD) 3 1. Adapted from Sartorius N.

J Clin Psychiatry

2. Kessler RC

et al. J Affect Disord

2001 (Suppl 15);8 –11; 1993;29:85 –96; 3. Zung W

et al. J Fam Pract

1993;37:337 –44.

Depression is associated with dysregulation of serotonin (5-HT) and noradrenaline (NA) in the CNS Prefrontal Cortex Limbic System

5HT and NA role in mental and physical processes

• Present in many mental and physical processes: • • • • • • • Anxiety 2 Pain perception 1 Vasoconstriction 1,2 Urethral sphincter contraction 2 Bladder wall relaxation 2 Gastrointestinal motility 2 Pilomotor contraction 2 1. Frazer A. J Clin Psychiatry 2001; 62(Suppl 12): 16–23 2. Stahl SM. Essential Psychopharmacology. 2 nd Edition. 2000. Cambridge University Press

A proposed model of symptoms mediated by 5-HT & NA* *Hypothetical neurobehavioural model using several data sources based mostly on animal studies 1. Lucki I.

Biol Psychiatry

2. Frazer A. 1998; 44: 151 –162.

J Clin Psychiatry

2001; 62(Suppl 12): 16 –23. 3. Jones CL.

Prog Brain Res

4. Ressler KJ, Nemeroff CB.

1991; 88: 381 –394.

Depress Anxiety

2000; 12(Suppl 1): 2 –19.

5-HT and Noradrenaline

Case Vignette

• A 33 year old married mother of two children presents to her GP with low mood, anhedonia, and diurnal variation in mood.

• How do you proceed to take a history and manage her symptoms?

Classifying depression

• There are two multi-axial classification systems in common use • Diagnostic Statistical Manual (DSM-IV) • American Psychiatric Association-derived • Used in the USA (particularly in clinical trials) • The International Classification of Diseases (ICD-10) • WHO-derived • Criteria used in UK and globally (but not in the USA) Gelder M et al. Shorter Oxford Textbook of Psychiatry. Oxford University Press 2001. Pages 96-100

ICD-10 criteria for depression The depressive episode must last for at least 2 weeks • • • • Low mood Reduced energy Reduced concentration Lack of self esteem / self confidence • • Guilt / worthlessness Tiredness • • • • • • • Loss of interest / pleasure Lack of emotion Altered sleep Morning depression Psychomotor retardation Loss of appetite / weight Loss of libido Gelder M et al. Shorter Oxford Textbook of Psychiatry. Oxford University Press 2001. Pages 271-272

DSM-IV criteria for depression

Five of the following symptoms during the same 2 weeks (must include A or B) A B Depressed mood present most of day and almost every day Loss of interest or pleasure in usual activities C Decreased energy or increased fatigability D Loss of confidence or self-esteem E Unreasonable feelings of guilt F Recurrent thoughts of death or suicide G Complaints of diminished ability to think or concentrate H Change in psychomotor activity, with agitation or retardation I Sleep disturbance J Change in appetite Gelder M et al. Shorter Oxford Textbook of Psychiatry. Oxford University Press 2001. Pages 271-272

NICE symptom classification for depression

NICE − National Institute for Clinical Excellence. Adapted from NICE guidelines, Management of depression, Dec 2004.

Treatment options for Depression

• • • • • • •

Pharmacological

Selective Serotonin Reuptake Inhibitors Noradrenergic and specific serotonergic antidepressant(NaSSA) Serotonin-Noradrenaline re-uptake inhibitors Tricyclic antidepressants Monoamine-oxidase inhibitors Combination/ augmentation therapies. Atypical antipsychotics.

• • •

Non-pharmacological

Psychotherapy: e.g. CAT, CBT, Psychodynamic, Interpersonal, Family Therapies Electroconvulsive therapy Vagus nerve stimulation, Transcranial magnetic stimulation and deep brain stimulation remain active avenues of investigation.

Nemeroff CB.J Psych Res 2006

Depression: Treatment goals

Treatment Goals Increase Remission Rates Prevent Relapse Restore Physical Functioning Restore Social Functioning Zajecka JM. J Clin Psychiatry 2003; 64 (suppl 15): 7-12

Treatment phases of depression

• Response 2 • Remission 3 • Recovery 1 • Recurrence 1 (≥50% reduction in HAM-D 17 (≤7 score on HAM-D 17 ) (Remission for significant period of time) (A new episode) 1.Kupfer DJ.

J Clin Psychiatry

1991;52 (5, Suppl): 28 –34 2.Fawcett J et al

J Clin Psych

3. Ballenger JC.

J Clin Psych

1997; 58(suppl 6):32 –38.

1999; 60(suppl 22):29 –34.

Key facts that patients should know

• • • • An episode should be treated for at least six months AFTER recovery.

Those with multiple episodes may need treatment in the longer term.

Anti-depressants are non-addictive and not known to cause new side-effects over time.

Anti-depressants should not be stopped suddenly due to possible discontinuation syndrome.

Maudsley Prescribing Guidelines 2005-2006

How would you proceed to treat this patient?

NICE guidelines summary

• • • • • Anti-depressants not recommended in mild depression.

SSRI first line of therapy.

Patients must be informed about the withdrawal effects of anti-depressants.

For severe or resistant depression, combination of CBT and anti-depressant recommended Patients with two prior episodes and functional impairment should be treated for at least two years

Selective Serotonin Reuptake Inhibitors (SSRI’s)

• • • • • Fluoxetine Sertraline Paroxetine Citalopram Escitalopram = = = = = Prozac Lustral Seroxat Cipramil Cipralex

Why SSRIs ?

• • • Safe (safer) in overdose Fewer side effects Start on a treatment dose

Case Review in OPC

• Patient comes back with increased agitation with medication, no better – if anything worse – and is now not really eating and spending most of the day inside • What would you advise?

Mirtazapine

Mirtazapine

• • Related to mianserin NaSSA • • • Presynaptic alpha-2 blockade Postsynaptic selective HT2 and HT3 blocker Also a potent histamine blocker

Mirtazapine

• Sedating – ? less so at higher doses • • Increased appetite ? Blood dyscrasias • BNF limit of 45mg, some use 60mg

Mirtazapine

Also: • • Relatively cardiac safe Not good for diabetes

Case continued…..

• Patient returns again – unable to tolerate increased appetite with mirtazapine so stopped it • What next ?

Options ?

• If problems related to S/E consider escitalopram • SNRI

SNRIs – Venlafaxine and Duloxetine

Venlafaxine

• • • SNRI only at doses of 225mg and above Max BNF limit of 375mg Some evidence for increased dose • • • S/Es of SSRIs Sweating, hypertension Cardiotoxic

Plot thickens

• Patient more severely depressed and showing no response to Venlafaxine.

• What do you think you are dealing with by this stage?

Treatment-resistant/refractory depression

• Term used in clinical psychiatry to describe cases of depression that do not respond to two adequate doses of anti-depressants prescribed for an adequate period of time.

• Review diagnosis, perpetuating factors (biological/psychosocial), compliance.

Tricyclic ?

• All have 3-ring structure • Discovered in 1950s in search for new antipsychotic

Tricyclics – how they work

Side effects

• • • • • • • Postural hypotension Dry mouth Blurred vision Urinary retention Weight gain Restlessness Insomnia

• Moclobemide – RIMA • • Phenelzine Tranylcypromine

MAOIs

MAOIs

• • • • • • • • • • • • • • •

Diet – avoid tyramine

Cheeses (except cottage cheese and cream cheese but includes cheese spreads), watch out for pizza !

Cream that is past its use-by date Meat and yeast extracts such as Marmite, Vegemite, Promite, Bonox, and Bovril Meats which have undergone an ageing process such as salami, game, pate, etc. (although fresh or frozen meats may be eaten) Caviar and smoked or pickled fish (e.g., pickled herrings) Stock cubes, packet soups, or commercial soup bases Soy products such as miso, and fermented soy bean, curd, or paste. Dehydrated meals (as these may contain stock cubes or similar) Sauerkraut and broad bean pods Banana skins, banana chips, or banana flavoured products (banana peel may be used in the flavouring) Excessive amounts of caffeine or coffee substitutes (e.g., Ecco) Protein drinks (e.g., Sustagen) Home brewed beer No more than 2 standard drinks per day of red wines, white wines, port, or manufactured beer Use only limited quantities of raspberries, raspberry jam, avocado, products made from unpasteurised milk, and soy sauce

Hypertensive Crisis

• Headache, dizziness, flushing, tachycardia, photophobia, chest pain • • • • Treat: EMERGENCY Phentolamine slow IV infusion Chlorpromazine can be used External cooling

Other alternatives

• • • • • • Lithium T3 Combination treatments ECT TMS, vagus nerve stimulation, deep brain stimulation.

Psychosurgery

Summary: Mechanisms of Action Anti-depressants

SRI NRI DRI α2 5-HT1a 5-HT 2 5-HT 3 ß block Citalopram Sertraline Venlafaxine Buproprion Nortriptyline Mirtazapine Buspirone X X X X X X X X X X

ELEMENTS AFFECTING RESPONSE Amount of improveme nt Effects of specific treatment* Non-specific treatment effects Spontaneous outcome *In most trials, about 30% more improvements on antidepressant than on placebo

Why can outcomes be ‘poor’ in depression?

• • • • • Under-recognition 1 Under-treatment 1,2 Poor treatment adherence 1 A total of 50% of patients receiving an initial prescription for an antidepressant stop treatment in the first month 1 Average drop-out rates are lower in trials of newer antidepressants compared with older agents (primarily tricyclic antidepressants) 1,3 Poor patient education 4 Lack of regular follow-up 1 1. Cassano P, Fava M. J Psychosom Res 2002; 53:849–857. 2. Hirschfeld RMA, Keller MB, Panico S, et al. JAMA 1997; 277(4):333–340.

3. Mulrow CD, Williams JW Jr, Chiquette E, et al. Am J Med 2000; 108(1):54–64.

4. ZajeckaJM. J Clin Psychiatry 2003; 64(Suppl 15):7–12.

Questions, comments?

STAR*D

Sequenced Treatment Alternatives to Relieve Depression

Structure

• • • • Effectiveness not Efficacy Trial Equipoise – stratified – Clinicians and patients decide together which arm to be randomised within Patients & Doctors not blinded (Some assessments blind) No Placebo

Inclusion Criteria

• • • HAM-D 17  14 Clinician deems antidepressant medication indicated 18-75 years of age

Exclusion Criteria

• • • • • • • Psychotic depression Current anorexia or OCD History of Bipolar / Psychotic disorder Currently taking anticonvulsants/ antipsychotics/ mood stabilisers / stimulants Intending to be or actually pregnant Breastfeeding Clear history of intolerance to any medications in first two levels

Level 1 Level 2

ADD

Buproprion SR or Buspirone or Cognitive Therapy Citalopram SWITCH TO Buproprion SR or Sertraline or Venlafaxine ER or Cognitive Therapy Level 2a Cognitive Therapy THEN Buproprion SR or Venlafaxine ER Level 3 Level 4

SWITCH TO

Mirtazapine or Nortriptyline

ADD

Lithium or Triidothyronine

SWITCH TO

Tranylcypromine or Mirtazapine & Venlafaxine

Flexible & Measurement Based Dosing

20mg for 4 weeks If QIDS >9 increase dose QIDS 6-8 increase or continue QIDS <5 continue If SEs address and continue or go to next level 40mg for 2 weeks If… 60mg

Level 1 Citalopram Level 2

ADD

Buproprion SR or Buspirone or Cognitive Therapy

SWITCH TO

Buproprion SR or Sertraline or Venlafaxine ER or Cognitive Therapy Level 2a Cognitive Therapy

THEN

Buproprion SR or Venlafaxine ER Level 3 Level 4

SWITCH TO

Mirtazapine or Nortriptyline

ADD

Lithium or Triidothyronine

SWITCH TO

Tranylcypromine or Mirtazapine & Venlafaxine

The Armamentarium cont.

• • •

Lithium Triidothyronine T3 Tranylcypromine –MAOI & amine releaser

Level 1

Responding to Citalopram

• • • • • • • 2876 patients with Ham-D ~21 28% Remission 47% Response 9% stopped due to intolerance 4% serious adverse effect 0 suicides Higher remission rates for well educated, employed, high income, married, Caucasian females. (i.e. me and my kind) Family history not predictive

Exit Doses

160 120 80 40 0 Mirtazapine Nortriptyline actual dose adequate dose max dose

Level 3

Augment T3=Lithium

&T3 &Lithium 45.2 micrograms T3 859.8mg of Li Lithium levels only assessed in 56.5% median 0.6meq/l

Level 3

Augment Li or T3

25% 20% 15% 10% 5% 0% T3 Li Lithium caused more exits due to intolerance

Evaluation of the generalizability of recent efficacy trials of antidepressants for MDD • • • • • • 86 % of study applicants were ineligible for the trials: 17 % had bipolar disorder, 16 % abused substances, 14 % had mild depression, 13 % had a medical contraindication, 12 % were using other psychotropic that were not permitted in the trial. These trials do not address the common clinical presentations seen in practice.