Medication management of depression
Stephen Bazire,Chief Pharmacist
Norfolk and Waveney Mental Health Partnership NHS Trust
Suicide
Suicide is a fatal outcome of psychiatric illness Suicide practically does not occur without the presence of
mental illness, most commonly depression, then alcoholism.
Depressed individuals who have committed suicide are seldom treated with antidepressants
Does increased antidepressant use reduces suicide?
14 studies say yes, 2 say no Effect may be even greater in bipolar disorder
where the lithium effect is greater Göran Isaacson, Acta Psychiatr Scand 2006;114:149-50
Effects of treating depression
Sweden: Two year educational programme (GPs on Gotland) Increased antidepressant use Reduced referral, sick leave and in-patient days for depression Significantly reduced suicide
(Rutz et al, Acta Psych Scand 1989;80:151-4) Sweden: Annual on-going educational programme (GPs in Jämtland county) Antidepressant use increased from 25% below national average to the
same level Suicide decreased to the national average
(Henriksson and Isacsson, Acta Psychiatr Scand 2006;114:159-67)Denmark: Suicide rate (1995-1999) has dropped in all groups More markedly in people prescribed SSRIs or older antidepressants
(n=438,625) Compared to those not treated with antidepressants (n=1,199,057)
(4yrs, Søndergård et al, Acta Psychiatr Scand 2006;114:168-76)
10% increase in SSRIs reduced suicide rate by 1.4%
10% increase in 2nd genn reduced suicide rate by 1.2%
Counselling vs antidepressants
Mild to moderate depression, community Antidepressants vs generic counselling 4 treatment groups:
Randomised to antidepressants or counselling (n=103) Patient preference to antidepressants or counselling
(n=103) No outcomes difference between groups (!)
Beck scores, Psychiatrists assessment Patients choosing counselling did slightly better than those
randomised to it Both seem equally effective in mild-to-moderate
depression (n=323, RCT, 8/52+12/12, Chilvers et al, BMJ 2001, 322, 722-75)
Drug-induced depression
Over 150 drugs reported to cause depression e.g:
Alcohol Benzodiazepines
e.g diazepam, clonazepam, temazepam, lorazepam
Antipsychotics Anticonvulsants
e.g. carbamazepine, lamotrigine, levetiracetam, pregabalin, topiramate
Anti-parkinsonian drugs Anticholinergics
H2 blockers Interferons (controversial) NSAIDs eg ibuprofen
Cardiovascular drugs e.g. beta-blockers, calcium
channel-blockers Antibiotics (rare) Baclofen (rare) Steroids (e.g. dexamethasone) Caffeine/caffeine withdrawal Oral contraceptives Simvastatin Dantrolene Tizanidine
Check doses, starting, stopping, previous
historyRef Psychotropic Drug Directory 2007, SPCs, BNF
Antidepressants available in UK
SSRIs: Citalopram (Cipramil), escitalopram (Cipralex), fluoxetine (Prozac), fluvoxamine (Faverin), paroxetine (Seroxat), sertraline (Lustral)
Mirtazapine (Zispin) Venlafaxine (Efexor) Tricyclics: amitriptyline, clomipramine (Anafranil),
dothiepin/dosulepin, doxepin (Sinequan), lofepramine (Gamanil), imipramine, maprotiline, nortriptyline, trimipramine (Surmontil)
Duloxetine (Cymbalta) Trazodone (Molipaxin) Reboxetine (Edronax) Moclobemide (Manerix) MAOIs: Phenelzine, isocarboxazid, tranylcypromine Mianserin, tryptophan, flupenthixol (Fluanxol) Agomelatine (2008), St. John’s wort
Comparative side effects of antidepressants
Anti-cholin-ergic
Cardiac Nausea Sed- ation
Over-dose
Pro-convuls-ant
Sexual dys- function
Tricyclics +++ ++ + ++ ++ + ++
(Es)citalopram (Cipramil/ Cipralex)
O O ++ O O O ++
Fluoxetine O O ++ O O O ++ Paroxetine (Seroxat) O O ++ O O O +++
Sertraline (Lustral) O O ++ O O O ++
Mirtazapine (Zispin) O O O ++ O O O
Reboxetine (Edronax) + + + O O O O
Duloxetine (Cymbalta) O O ++ O ? ? ++
Trazodone (Molipaxin) + + +++ ++ + O ++
Venlafaxine (Efexor) O ++ +++ + ? + ++
Bupropion (Zyban) + O + O ++ +++ O
MAOIs ++ ++ ++ O/+ ++ O +
Agomelatine (TBA)
Modes of action and receptors
SSRIs - 5-HT reuptake inhibitionMirtazapine - increased 5-HT and NE availability, 5-HT2 and 5-
HT3 antagonismVenlafaxine and duloxetine - 5-HT and NA reuptake inhibition
(venlafaxine variable, duloxetine similar)
Trazodone - 5-HT reuptake inhibition and some receptor antagonism
Tricyclics - 5-HT and NE reuptake inhibitionReboxetine - noradrenaline reuptake inhibitionFlupenthixol - Autoreceptor inhibitionMoclobemide - Reversible MAO-A inhibitionMAOIs - Inhibition of MAO-A and MAO-B enzymesAgomelatine - 5HT2C/2B antagonist and melatonin M1/2 agonist
Relevance: as long as it works, side effects
Selected antidepressant side effects
Anticholinergic – dry mouth, blurred vision, constipation Cardiac – prolonged QTc, postural hypotension, tachycardia, Nausea – initial, start with lower doses Sedation - mostly histaminergic effect Overdose toxicity – cardiac Pro-convulsant – bupropion at >300mg/d Sexual dysfunction – lower libido, ED, anorgasmia Anxiety (short-term esp. with SSRIs), appetite changes,
hyponatremia (except mirtazapine), diarrhoea, headache, sweating (esp. at night)
Many can be minimised by starting at lower doses In Mirtazepine, if a patient is too drowsy on the 15mg dose, push UP to
the 30mg dose. I know this sounds illogical, but the 15mg dose is more drowsier than the 30mg (there is a pharmakinetic reason
behind this)
Usual therapeutic doses for depression
SSRIs: Citalopram (Cipramil) 20-40mg Escitalopram (Cipralex) 10mg Fluoxetine (Prozac) 20mg fluvoxamine (Faverin) 150-300mg? Paroxetine (Seroxat) 20-30mg Sertraline (Lustral) 50-100mgTricyclics: amitriptyline, clomipramine
(Anafranil), dothiepin/dosulepin, doxepin (Sinequan), imipramine, nortriptyline, trimipramine (Surmontil) – 125-150mg/d
Lofepramine (Gamanil) 140-210mg
Newer: Mirtazapine (Zispin) 30-45mg Venlafaxine (Efexor) 75-225mg Duloxetine (Cymbalta) 60-
120mg Trazodone (Molipaxin) 150mg? Reboxetine (Edronax) 8-12mg Moclobemide (Manerix) 300mgMAOIs: Phenelzine 45mg? Isocarboxazid 30mg? Tranylcypromine 30mg? Mianserin, tryptophan,
flupenthixol (Fluanxol), agomelatine (soon)
St. John’s wort
Onset of action of antidepressants
“Antidepressants take 4 weeks to work”Wrong!
23% of all drug-placebo differences occur within the first week and 57% were apparent by week 2
(s=47, n=8500, d/b, p/c, Pasternak and Zimmerman, J Clin Psych 2005, 66, 148-58) “Time to substantial remission” may take 4 weeks in
clinical trials and that is why doctors usually say “it may take up to 4 weeks to see whether it works or not” (which is the right thing to say)
In 90% cases substantial improvement occurs within the first 2 weeks but that the benefit continues to build over several weeks.
(review by Mitchell, B J Psych 2006, 188, 105-6)
Markers of antidepressant response
• If no improvement (even minimal) after 4 weeks of a therapeutic dose, should switch to another one
• With minimal improvement, continue until week 6 but there is only benefit in continuing in about 10% pts
(n=593, Quitkin et al, Arch Gen Psychiatry 1996, 53, 785-92
If there is no response by 8 weeks then the trial should “be declared a failure”
(n=840, 12/52, open, Quitkin et al, Am J Psych 2003, 160, 734-40)
Only 58% people take antidepressants for more than 28 days
(n=829, Offson et al, Am J Psych 2006, 163, 101-8).
Duration of antidepressant therapy summary
40% of people may relapse after an index depressive episode within 2 years, and 60% within 5 years
First episode: Six months after recovery at same dose minimises risk
of relapse(n=839, RCT, one-year, Reimherr et al, Am J Psych 1998, 155, 1247-53
Second episode: 1-2 years
Third or subsequent episode: 3-5 years or longer
(Frank and Kupfer, Arch Gen Psych 1990 and 1992)
Depression relapse prevention
Full-dose vs. half-dose tricyclics
Frank et al, J Aff Dis 1993, 27, 139-45
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20
40
60
80
100
0 6 12 18 24 30 36Months
% r
emain
ing w
ell
Full-dose TCA
Half-dose TCA
Relapse prevention
Frank and Kupfer, Arch Gen Psych 1990 and 1992
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20
40
60
80
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0 6 12 18 24 30 36 42 48 54 60Months
% s
till w
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Full-dose3-yr switchPlacebo
Discontinuing or switching antidepressants
Why discontinue or switch antidepressants?
Lack of efficacy Adverse effects Patient discontinues of own accord End of maintenance phase
What you can do if there is alack of response
1. Increase the dose 2. Switch antidepressants 3. Augment with:
another antidepressant mood stabiliser anxiolytic another drug e.g. pindolol, thyroxine
etc
1. Increasing the dose- types of dose-efficacy relationship
0
10
20
30
40
50
60
70
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FlatCurvilinearLinearTherapeutic windowStepped
Summary of dose-response curves
Dose-efficacy Concentration-efficacy
Data Result Data Results
Tricyclics + Curvilinearor linear
+++ Linear, flat,curvilinear ortherapeuticwindow
MAOIs + N/K + Flat
SSRIs +++ Flat ++ Flat
Venlafaxine +++ Curvilinearor linear
++ Linear
Mirtazapine N/K N/K N/K N/K
Fluoxetine fixed-dose study
0
10
20
30
40
50
60
70
Placebo 5mg 20mg 40mg
ResponseRemission
Altamura Altamura et al, B J Psychet al, B J Psych 1988, 1988, 153153(Suppl 3), 109-(Suppl 3), 109-112112
Fluoxetine fixed-dose study
0
10
20
30
40
50
60
Placebo 20mg 40mg 60mg
ResponseRemission
Altamura Altamura et al, B J Psychet al, B J Psych 1988, 1988, 153153(Suppl 3), (Suppl 3), 109-112109-112
Venlafaxine dose-response
0
10
20
30
40
50
60
70
80
Placebo 75mg 225mg 375mg
Response at 6weeksRemission at 6weeks
Rudolph Rudolph et al, J Clin Psychiatryet al, J Clin Psychiatry 1998, 1998, 5959, 116-, 116-122122
The chances of success with increasing dose:
Limited: SSRIs (generally side effects limited) Mirtazapine (unknown)
Possible: Tricyclics (side effects increase) MAOIs (side effects and toxicity increase)
Probable: Venlafaxine (side effects increase)
Switching antidepressants
Factors to consider: Speed at which the
switch is needed Current dose of the
first drug Individual drugs
effects, transmitter effects, kinetics etc
Individual susceptibility to (additive) side-effects
Potential problems: Cholinergic rebound Antidepressant
discontinuation symptoms
Drug-drug interactions Discontinuation effects
from first drug interpreted as side-effects of the second
Serotonin Syndrome for drugs affecting serotonin
Serotonin syndrome
Definition - a toxic state caused by an increase in brain serotonin activity.
Symptoms 1. Neuromuscular
Restlessness Myoclonus Tremor and rigidity Hyperreflexia
2. Others Shivering/elevated temperature Arrhythmias etc.
Can be fatal due to cardiac collapse
Causes Most often with combined or consecutive treatment with SSRIs, tricyclics, MAOIs, tryptophan etc
Treatments Stop drugs - usually
resolves in no more than 24 hours
Symptomatic measures e.g. cooling, BDZs
Prevention take care when combining
or switching serotonergic antidepressants
Discontinuation phenomena
Characteristics: Commence within 1-3 days of stopping or
reducing doses Usually short-lived (1-2 weeks) Rapidly suppressed by re-introduction of
drug Distinct from relapse or recurrence, which
occur 2+ weeks after discontinuation Can occur even with missed doses
Discontinuation symptoms
Tricyclics: Cholinergic rebound
headache, restlessness, diarrhoea, nausea
‘flu-like symptoms, cramps lethargy sleep disturbances movement disorders
SNRI (venlafaxine): Fatigue, headache,
restlessness, nausea abdominal distension,
congested sinuses
“SSRI discontinuation”: Dizziness, light-headedness Sleep disturbances agitation, volatility electric shocks in the head nausea, fatigue, headache ‘flu-like symptoms
Mirtazapine & reboxetine: Little or nothing reported MAOIs: Confusion, delirium,
psychosis
Paroxetine discontinuation
0
20
40
60
80
100
120
Time since last dose
Pla
sma leve
l Daily paroxetine
ParoxetinediscontinuationNormal decay
“MedEd” technique
Craving? Tolerance? Withdrawal? Immediateeffect?
Alcohol
Opiates
Caffeine
Nicotine
Cannabis x
Hypnotics x
Antidepressants x ? () x
Antipsychotics x x () ()
Lithium x x x
Insulin x x ()
Depression in bipolar disorder
Bipolar depression: is more resistant and longer-lasting
up to 50% may still be depressed at one year (Hlastala et al, Depress Anxiety 1997, 5, 73–83)
may respond to mood stabilisers e.g. lithium, valproate, carbamazepine etc
is susceptible to manic switch, especially in first 12 weeks
use lowest switch risk drugs, eg. SSRIs, mirtazapine Beware of inducing a mixed state in bipolar III
risk of self-harm/suicide is high
Antidepressants in bipolar depression
Antidepressant (paroxetine <40mg/d or bupropion <375mg/d)
or placebo plus Mood stabiliser (lithium, valproate, carbamazepine or a
licensed antimanic agent e.g. olanzapine, risperidone, aripiprazole, quetiapine, ziprasidone)
Outcome aim was 8/52 euthymia: Mood stabiliser and antidepressant response 23.5% Mood stabiliser and placebo response 27.3%
Longer-term adjunctive antidepressants have no therapeutic advantage
but at least the antidepressant did not increase the risk of relapse or switch to mania nor have greater ADRs
(n=366, RCT, d/b, p/c, 26/52, STEP-BD, Sachs et al, N Engl J Med 2007;356:1-12)
Quetiapine in bipolar depression
BOLDER 1 n=542, MD episode in
Bipolar I or II Response
600mg/d = 58.2% 300mg/d = 57.6% placebo = 36%
Remission 52.9% vs 28.4% Treatment emergent mania
3-4% for both groups
(n=542, RCT, d/b, p/c, 8/52, Calabrese et al, Am J Psych 2005,
162, 1351-60)
BOLDER 2 Quetiapine 300mg and
600mg/d monotherapy equally effective in bipolar I and II depression
53% response in BD
(n=542, RCT, 8/52, p/c, Hirschfeld et al, J Clin Psychiatry
2006;67:355-62).
Lamotrigine
Lamotrigine 50–200mg/d monotherapy significantly more effective than placebo in bipolar I depression
n=195, RCT, Calabrese et al, J Clin Psychiatry 1999, 60, 79–88
Survival rates favoured lamotrigine, with 41% stable without relapse at 6/12 (cf 26% placebo)
Well-tolerated, may thus be useful in some rapid-cyclers n=324, open + n=182 d/b maintenance phase,
Calabrese et al, J Clin Psych 2000, 61, 841-50
Two unpublished, negative studiesUnlicensed in UK, and never will be
NICE mentioned for relapse prevention of bipolar depression
Conclusion
Depression is a chronic condition and antidepressants:
are effective in acute depression prevent relapse are not addictive nor dependence prone help correct a chemical imbalance have no major documented long-term harmful effects appear to be widely used sub-optimally
Resistant depression might be undiagnosed bipolar Education about antidepressant use should be integral
with all prescribing, as it improves attitudes and hence “concordance”