TREATMENT RESISTANT DEPRESSION

TREATMENT RESISTANT DEPRESSION

Dr. B C MALTHESHJR-3

BJGMC

1-year prevalence of 3–5%, Lifetime

prevalence varying from 10 to 30% [Hasin et al. 2005; Waraich et al. 2004].

Depression is ranked by the WHO as the 3rd highest cause of disability across the world.

Projected to become the second by 2020 [Murray and Lopez, 1997; World Bank, 2004].

Epidimiology

Remission >75%

Response 50% - 74%

Partial Response25% - 49%

Nonresponse <25%

Recovery – failure to meet criteria for MDD for at least 8 wks.

Operational definitions of treatment response

Operational definitions of treatment response

STAR*D Cumulative Remission Rates

0

10

20

30

40

50

60

70

80

Level 1 Level 2 Level 3 Level 4

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Gaynes B, et al. Clev Clin J Med. 2008;75(1):57-65.

33%

50%

63%67%

Only a third of patients achieve full remission

after their first antidepressant treatment in naturalistic conditions [Rush et al. 2006]

30-45% - Fail to respond to adequate trial of antidepressant. 10-15% - show partial response. 20-35% - are nonresponsive

Rates of Response

High risk of relapse and recurrence TRD is more likely to cause suicide or a suicide

attempt, Confers poor prognosis kindling, episode

frequency increases. Poor functioning (e.g., work, family) Psychiatric or general medical complications

(e.g., substance abuse) Increased Health service utilization Death from Medical comorbidities also

increase

Is Achieving Remission Important?

Poorly defined term

Failure to respond to a trial of more than one antidepressant drug in a dose equivalent to 250-300 mg of IMN given for duration of 6-8 wks.

Unremitting depression despite treatment with at least 2 different antidepressant or an antidepressant & a course of ECT.

Definition of TRD

Failure to respond to 2 adequate trials

(adequate dosage for adequate duration) of different chemical classes.

Several Staging Methods Thase & Rush (1997) Massachusetts General Hospital CPMP Guidelines

Definition of TRD

STAGE I

FAILURE OF AT LEAST ONE ADEQUATE TRIAL OF ANTI DEPRESSANT MONOTHERAPY

STAGE IISTAGE I +FAILURE OF TRAIL OF DIFFERENT ANTIDEPRESSANT CLASS

STAGE III STAGE II +FAILURE OF TRAIL OF TCA

STAGE IV STAGE III +FAILURE OF TRIAL OF MAO-I

STAGE V STAGE IV +FAILURE OF ECT COURSE

Thase and Rush stages

Incorrect primary diagnosis

Is there any other primary Psychiatric disorder (e.g., substance-induced mood disorder) not being treated?

Is there a primary medical condition not being treated? Is there an unrecognized depressive subtype?

Psychotic depression Bipolar depression

Depressive severity Chronicity of depression (illness lasting 2 years or more) Greater number of somatic symptoms History of childhood emotional abuse and sequelae

Causes of Resistance

Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004

Factors related to antidepressant treatment Inadequate treatment of earlier episodes may

lead to kindling and sensitization at the receptor/synaptic levels leading to the development of resistance.



Primary Medical diagnosis -hypercholesterolemia,

hypothyroidism, diabetes, Cushing’s syndrome, Parkinson’s disease, Huntington’s disease, cerebrovascular disease, and seizure disorder.

Comorbid psychiatric disorders Anxiety disorders

Commonly coexist with major depression Increase the likelihood of more severe depressive

symptoms, suicide attempts, decreased responsiveness, and greater susceptibility to side effects

Substance abuse Personality disorders Eating disorders



Patient factors

Compliance Individual differences in drug metabolism Nutritional status - deficiencies in folate,

thiamine, vitamin B6, vitamin B12, copper, and zinc

psychosocial stressors and poor social support. Physician factors

Underdosing Inadequate length of treatment


Pseudo resistance


Re-evaluation of pts history & presentation Assessment of treatment adequacy

Dose Duration Drug compliance Drug monitoring

Treatment strategies – Pharmacological - optimization, augmentation,

combination, switching. Somatic treatments. – DBS, VNS, rTMS Non pharmacological.

Management

Ensure that the current drug is being used for

sufficient duration(6-8 weeks), at the ideal dosage with maximum adherence.

Does may have to be decreased or increased Address adherence issues by using pill dairy or

pill counts or supervised medications.

Optimization

• Augmentation – adding an agent that is not

conventionally used as monotherapy to an existing antidepressant.

• Advantages – rapid onset of action, no withdrawal sxs, no loss of partial response.

• Disadvantage – drug-drug interaction, increased cost, compliance.

Augmentation strategies

Lithium

0.5 - O.8 meq/lt Most of the literature available is regarding TCA

augmentation with Lithium, sparse data available on SSRI augmentation with Lithium

Side effects monitoring and blood level monitoring has to be done stringently.


Philip et al.,Pharmacologic Approaches to Treatment Resistant Depression: A Re-examination for the Modern Era; Expert Opin Pharmacother. 2010 April ; 11(5)

Triiodothyronine (T3) – 20-50 micg/day

generally well tolerated and has a favourable side effect profile compared to lithium.

Similar to lithium augmentation, much of the data supporting thyroid augmentation comes from studies with TCA

Repeat TFTs may be needed Antiepileptic drugs

Valproate, CBZ, Lamotrigine Pindolo (5mg TDS)

Mainly to accelerate the response than to overcome resistance


Olanzapine, Quetiapine (300-600mg/day) and to some

extent aripiprazole (5-20mg/day) have good supportive data from controlled clinical trials as augmenters of SSRIsEg: Olanz + Floux combination

Data for risperidone (0.5-2 mg/day) are not robust, but can be used as an augmenting agent

Research supporting the augmentation effects of ziprasidone is much more limited

Use of Clozapine is limited due to its adverse effect profile, but can be used as last resort after other Aps fail

Atypical antispychotics

RC Shelton, GI Papakostas - Augmentation of antidepressants with atypical antipsychotics for treatment‐resistant major depressive disorder Acta Psychiatrica Scandinavica, 2008

Amphetamine, Methylphenidate, Modafinil can

be used Methylphenidate enhances Dopaminergic

transmission and has euphorigenic action Stimulants mainly decrease fatigue and

apathy Risk of abuse in patients with history of

substance use disorder.

Stimulants as Augmenting drug

Summary of Augmentation options

The use of at least 2 antidepressants that have well

established efficacy.

Advantages & disadvantages similar to augmentation.

SSRI + bupropion / Buspirone.

TCA + SSRI.

SSRI or SNRI can be combined with Mirtazapine / trazodone.

SSRI + SNRI I not a good combination

TCA & MAOI may lead to seratonin syndrome.

SSRIs, venlafaxine, or clomipramine should not be combined with MAOIs

Combination therapy

Switching can be either within same class or between

two classes of drugs.

Advantages – improved compliance, fewer adverse effects, cost effective.

Disadvantages – withdrawal sxs, time lag between initiation of new drug & treatment response.

Switching to older class of drug can also be done like : SSRI TCA or SSRI MAOI,

Switching Strategies

Philip et al.,Pharmacologic Approaches to Treatment Resistant Depression: A Re-examination for the Modern Era; Expert Opin Pharmacother. 2010 April ; 11(5)

SSRI ► SSRI (Zarate et al, 1996)

SSRI ► SNRI (Poirier&Boyer,1999)

SSRI ► Bupropion (Fava et al, 2003)

SSRI ► TCA (Fava, 2001)

SSRI ► MAOI (Thase & Rush, 1995)

Switching Strategies

Al-Harbi ., Treatment-resistant depression: therapeutic trends, challenges, and future directions.; Patient Preference and Adherence 2012:6 ,369–388

Response rate 26%–76%; remission rate 28%–

87%. TCA might prove to be a strategy of first choice

for patients who do not respond to an SSRI; Intolerance to one SSRI does not necessarily

mean intolerance to the whole class of SSRI; Between-class switch is a good treatment option. In patients unresponsive to SSRI, administration

of antidepressants with different mechanisms of action is an effective switching strategy.

Summary of the findings of the above studies

24 studies (n = 1092 patients) compared active

& sham rTMS in TRD Active rTMS was significantly superior to sham

conditions in producing clinical response. The pooled response and remission rates were

25% and 17%, and 9% and 6% for active rTMS and sham conditions, respectively.

Relatively low response and remission rates, the short durations of treatment, and the relative lack of systematic follow-up studies suggest that further studies are needed.

rTMS for Treatment Resistant Depression

Lam RW, Chan P, Wilkins-Ho M, Yatham LN. Repetitive transcranial Magnetic stimulation for treatment resistant-depression: a systematic review and metaanalysis. Can J Psychiatry 2008 ; 53(9): 621-31.

DBS for TRD is an experimental area of

investigation. costs and the risks related to the surgical

procedure are limiting factors, Used only in most treatment-refractory cases

of depression. The data on efficacy in TRD are limited to a

series of open-label studies. DBS is not a treatment indicated for acute

worsening, as the effects of stimulation can take weeks to months to manifest.

DBS for Treatment Resistant Depression

Cusin and Dougherty, Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS., Biology of Mood & Anxiety Disorders 2012, 2:14

Useful in case of mild to moderate treatment

resistance, but not in severe resistance VNS is usually considered as an adjunct to

pharmacologic treatment, and it can safely be combined with ECT in case of an acute relapse

VNS for Treatment Resistant Depression

Cusin and Dougherty, Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS., Biology of Mood & Anxiety Disorders 2012, 2:14

Leads are placed through a burr hole in the skull but

above the dura mater and thus remain separated from the underlying cortical region by the arachnoid space.

ECS is more direct than transcranial magnetic stimulation (TMS) or vagus nerve stimulation (VNS) and potentially safer than deep brain stimulation (DBS),

Appears relatively safe, feasible. Five adults with an average of 5.8 failed antidepressant

treatments and currently depressive episode were enrolled

At 7 month follow up 3 had reached remission, almost all had shown response

Bilateral Epidural Prefrontal Cortical Stimulation (ECS) for

TRD

Nahas et al.,Bilateral Epidural Prefrontal Cortical Stimulation for Treatment Resistant Depression; Biol Psychiatry. 2010 January 15; 67(2):

Efficacy of CBT was analyzed in STAR-D study.

CBT is both an acceptable switch and augmentation option in the second step of STAR-D

Benefit of CBT as augmentation was slower (up to 3 weeks) compared to augmenting with medication.

Cognitive Behavioral Therapy

Ketamine acts as antagonist at NMDA

receptor, potentiates transmission at AMPA, Increased stress hormones in depression leads

to disruption in hippocampal LTP, which is NMDA dependent process.

Acts on m-TOR pathway to leading to increased synaptic signaling

Increases BDNF concentration Through these mechanisms it causes

enhanced synaptic plasticity

Ketamine Mechanism of action

Murrough et al.,Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression; Biol Psychiatry. 2013 August 15; 74(4)

24 patients of TRD were selected They underwent a washout of antidepressant medication followed

by a series of up to six intravenous (IV) infusions of ketamine (0.5 mg/kg) over 12 days.

Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion.

Overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery–Asberg

Depression Rating Scale (MADRS) score at two hours following the first ketamine infusion

Suicidal ideation (SI) rapidly decreased within 6 hours of 1st infusion, even among study non-responders.

But even Among responders, median time to relapse following the last ketamine infusion was 18 day

Ketamine infusions for TRD

Murrough et al.,Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression; Biol Psychiatry. 2013 August 15; 74(4)

Six studies (1996-2010) have investigated the effect of

adjunctive dopamine agonists in the treatment of refractory depression

These studies have generally found marked improvement in depressive symptoms. however, most of these studies targeted stage I treatment-resistant depression, with only one study for stage II refractory depression which evaluated Pramipexole.

It is thus suggested that pramipexole augmentation, among various dopamine agonists, may be a worthwhile option for refractory depression.

Dopamine Agonists for TRD

Hori H et al.,The Efficacy of Pramipexole, a Dopamine Receptor Agonist, as an Adjunctive Treatment in Treatment-Resistant Depression: An Open-Label Trial.; The Scientific World Journal Volume 2012,

Used as an Augmenting agent SAM-e has shown antidepressant efficacy that

is superior to placebo and equivalent to the effects of TCAs in a meta- analytic studies.

S-adenosyl metheonine for TRD

Seo RJ et al.,Atypical Antipsychotics and Other Therapeutic Options for Treatment of Resistant Major Depressive Disorder.; Pharmaceuticals 2010, 3, 3522-3542

Agomelatine Agonist at MT1 & MT2.. Antagonist at 5HT2C Given 25mg/day in HS dosage.

Melatonin Receptor Agonists

There is blunted ACTH response to CRH. Dysregulation of the HPA axis has been found

to be linked to nonresponse to antidepressants and relapse following successful treatment.

Metyrapone – a cortisol synthesis inhibitor, targeted at altered HPA axis.

With repeated administration of Metyrapone the plasma cortisol level normalises and the ACTH levels increase to normal level.

Metyrapone in treatment-resistant

depression

Ther Adv Psychopharmacol (2012) 2(4) 139 –149

Rogoz and colleagues did a open-label trial of

augmentation of imipramine with metyrapone in patients with TRD.

Patients were treated with imipramine for first 6 weeks, followed by 6 weeks of the addition of metyrapone (250 mg twice daily) treatment

Metyrapone augmentation significantly reduced the scores on the depression rating scales [HDRS (46%) and Beck Depression Inventory (39%)].

Rogoz, Z., Skuza, G., Wojcikowski, J., Daniel, W.A., Wrobel, A., Dudek, D. et al. (2004) Effect of metyrapone supplementation on imipramine therapy in patients with treatment-resistant unipolar depression. Pol J Pharmacol 56: 849–855.


depression

Jahn et al did a double-blind randomized,

placebo-controlled study of augmentation of serotonergic antidepressants with either metyrapone or placebo for 3 weeks.

At 5 weeks post intitiation of the study, metyrapone (1gm) group showed significantly more improvement in HDRS scores compared to placebo group .


depression

Jahn, H., Schick, M., Kiefer, F., Kellner, M., Yassouridis, A. and Wiedemann, K. (2004) Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial. Arch Gen Psychiatry 61: 1235–1244.

It has got few direct neurobiological actions

mediated through a non-haematopoietic Epo receptor situated in the brain.

Systemically administered Epo crosses the blood-brain barrier (BBB) and has neuroprotective and neurotrophic effects in animal models of acute brain damage and chronic neurodegenerative conditions.

With Epo administration there is rapid up-regulation of neuroplasticity mechanisms including BDNF and neurogenesis, and anti-inflammatory actions.

Erythropoietin in treatment-resistant

depression

Miskowiak et al (2007-2008) 4 articles on the effect of erythropoeitin on mood,

cogniotion, face detection Epo improves recognition of all facial expressions,

in particular of low intensity happiness. This is similar to behavioural effects observed with acute administration of serotonergic antidepressants.

Epo improved self-reported mood for all 3 days post-administration.

Epo directly modulates brain responses to emotional information in humans in a manner consistent with the actions of conventional antidepressants.


depression

Miskowiak et al. Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder Trials 2010, 11:97

One ongoing study to assess the effects of

long term administration of Epo. Results are awaited.

Miskowiak et al did a double-blind, placebo-controlled, parallel-group design.

40 patients with treatment-resistant major depression are recruited and randomised to receive weekly infusions of Epo (Eprex; 40,000 IU) or saline (NaCl 0.9%) for 8 weeks.

The primary outcome parameters for the two studies are: depression severity measured with the Hamilton Depression Rating Scale 17 items (HDRS-17).


depression

Miskowiak et al. Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder Trials 2010, 11:97

Summary

A working definition of TRD:

Failure to remit after 8-12 weeks at a adequate doseage

Key considerations with TRD Clarify diagnosis and potential risk factors for

persistence Patient factors: compliance and/or rare

pharmacokinetics Physician factors: underdosing and/or

inadequate treatment length

Summary

No clear direction for augmenting vs. switching Each appear successful for ~ 50% of

patients If patient tolerating, first try to maximize

dose When switching antidepressants after one

failure, within class or different class choices are reasonable

Available evidence supports lithium and T3 as most effective augmenting agents

We Have Little Evidence Guiding Treatment Choice After

the first drug fails

We Have No Evidence For Those with Two or More Treatment Failures

We Do Not Know Where Psychotherapy is helpfull Reviews suggest that psychotherapy plays a significant

role in the management of treatment resistant depression We do not know about the benefits of switching to

psychotherapy compared to augmenting medications with psychotherapy

Vast majority of studies excluded patients with common general medical and psychiatric comorbidities

Summary – We don’t know

Hasin, D.S., Goodwin, R.D., Stinson, F.S. and Grant, B.F. (2005) Epidemiology of

major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch Gen Psychiatry 62: 1097–1106.

Waraich, P., Goldner, E.M., Somers, J.M. and Hsu, L. (2004) Prevalence and incidence studies of mood disorders: a systematic review of the literature. Can J Psychiatry 49: 124–138.

Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., Warden, D. et al. (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163: 1905–1917.

Rogoz, Z., Skuza, G., Wojcikowski, J., Daniel, W.A., Wrobel, A., Dudek, D. et al. (2004) Effect of metyrapone supplementation on imipramine therapy in patients with treatment-resistant unipolar depression. Pol J Pharmacol 56: 849–855.

Jahn, H., Schick, M., Kiefer, F., Kellner, M., Yassouridis, A. and Wiedemann, K. (2004) Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial. Arch Gen Psychiatry 61: 1235–1244.

References

Miskowiak K, O'Sullivan U, Harmer CJ: Erythropoietin reduces neural and

cognitive processing of fear in human models of antidepressant drug action. Biol Psychiatry 2007, 62:1244-1250.

Miskowiak K, O'Sullivan U, Harmer CJ: Erythropoietin enhances hippocampal response during memory retrieval in humans. J Neurosci 2007, 27:2788-2792.

Miskowiak K, Inkster B, O'Sullivan U, Selvaraj S, Goodwin GM, Harmer CJ: Differential effects of erythropoietin on neural and cognitive measures of executive function 3 and 7 days post-administration. Exp Brain Res 2008, 184:313-321.

Miskowiak K, Inkster B, Selvaraj S, Wise R, Goodwin GM, Harmer CJ: Erythropoietin improves mood and modulates the cognitive and neural processing of emotion 3 days post administration. Neuropsychopharmacology 2008, 33:611-618.

References

Health & Medicine

TREATMENT RESISTANT DEPRESSION