Treatment Resistant DepressionAnita S. Kablinger, M.D.

Associate ProfessorDepartments of Psychiatry

and Pharmacology

TRD Terminology• Non-response: poor response requiring a

change in treatment plan (<50% HAM-D)• Response: good enough response so that

a change in treatment isn’t necessary• Remission: 2 consecutive months of an

asymptomatic stage (HAM-D ≤ 7)• Recovery: ≥ 6 months of remission• T-resistant D: partial response to

treatment; patient meets non-response criteria

• T-refractory D: no response to treatment; symptoms are unchanged or worse

Statistics

• 60-70% tolerant patients respond to

1st line monotherapy• Up to 50% treated with single

antidepressant don’t reach full remission • 1/3+ become treatment resistant

Predictors of Non-Response

• Axis II personality disorders

• Anxiety comorbidities

• Delays in initiating treatment or chronicity

• Substance abuse

• +Family history

• Extremes in age of onset

• Depression subtypes

TRD - Common Diagnosis• No clearly defined criteria• Often misdiagnosed - primary and secondary (organic) causes should be determined• Often inadequately treated - treatment response criteria (dose, duration, compliance) - # of trials before labeled non-responsive

Pseudoresistant

• Inadequate dosing/ early treatment discontinuation

• Patient noncompliance

• Misdiagnosis

Assessing Treatment Outcome

• Comorbidity

• Psychosocial Stressors

Current TRD “criteria”

No response after:

• Maximum tolerable dosage

-varies depending on patient

-affected by pharmacokinetics

• 4-6 weeks

Paradigms Which Contribute to Faulty TRD Labeling

• Failure to diagnose and manage bipolar

• Failure to diagnose and manage psychotic

• Failure to diagnose and manage melancholic depression

• Diagnosing and/ or managing non-melancholic as melancholic depression

• Misdiagnosing secondary depression

• Failing to identify organic determinants– Parker et al 2005, J of Affect Dis

TRD

*-Accurate diagnosis

-Different classes of antidepressants are more effective for specific forms of depression

-Some forms of depression have longer recovery times

-Some medical conditions contribute to TRD• Treatment response criteria • # of adequate trials required• Adequate treatment guidelines

TRD Current Guidelines

• CPMP Guidelines

• Thase and Rush Staging Model

• Massachusetts General Hospital Staging Method

• Souery et al Operational Criteria

CPMP GuidelinesCommittee for Proprietary

Medicinal Products

• “Consecutive treatment with 2 products of different classes, used for a sufficient length of time at an adequate dose, fail to induce an acceptable effect”

• Dose and duration undefined

Thase and Rush Staging Model• I: Failure of at least 1 adequate trial of 1 major

class of antidepressant• II: Stage I resistance + failure of an adequate

trial of an antidepressant in a different class

from that used in stage I• III: Stage II resistance + failure of adequate trial

of TCA• IV: Stage III resistance + failure of adequate trial

of MAOI• V: Stage IV resistance + failure of a course of

bilateral ECT

T and R model (cont.)• Dosing and duration of each trial aren’t

thoroughly explained• Stage I: Does no response to 1 trial mean resistance? What about 2 consecutive SSRI trials? (Patient may be resistant to particular compound but not to all in that class)• Implies hierarchy of treatment• Implies greater difficulty in treating non-response

after 2 trials of agents from 2 diff classes than with 2 trials from same class

• No combo/ augmentation strategies considered

Massachusetts General Hospital Staging Method

• Quantitative with continuous variable• Considers # of failed trials + intensity and

optimization of treatments• No antidepressant hierarchy assumed• Includes augmentation/ combo treatments • More predictive of remission than T and R

method

Souery et al Operational Criteria

• Similar to MGH Method

• 2 consecutive failed trials required

• Addresses chronic resistant depression which may develop after 1 year of

non-response to multiple therapies

StudiesMore studies necessary for:

-current staging models

-non-response and resistance predictors

-effectiveness of current strategies:

optimization of dose

combo/ augment therapy

switching therapy

Current (or future) Treatment Options

• Vagus Nerve Stimulation• Triple Reuptake Inhibitors• Antidepressant Augmentation• Lithium• Atypical Neuroleptic Augmentation • Novel Antipsychotics• Med Switches• Augmentation/ Combination Treatments

Triple Reuptake Inhibitors (TRI)

• Target all three of brain’s monoamines

(serotonin, norepinephrine, dopamine)

• Expected on the market by 2010

• Better efficacy and tolerability, faster acting, less side effects, treats broader range of symptoms

Antidepressant Augmentation

• Whites, young, previous hospitalization, comorbidities are more likely to receive augmentation

• Most common augmenting agents:

-2nd antidepressant

-2nd generation antipsychotic

* why not lithium

Lithium

• Most research support

• Least used – Used more often in whites and those with

previous hospitalizations than in others

Low Use of Lithium• Concerns about safety, convenience,

tolerability, stigma– Therapeutic doses close to toxic levels– Med/ blood level monitoring– Early side effects

• Potential diminishing efficacy with SSRI– Popularity of SSRI to replace tricyclic agents– Efficacy with tricyclic agents

• Lack of advertising– Dated articles and studies

Atypical Neuroleptic Augmentation

• Olanzapine, Risperidone, Quetiapine, Ziprasidone

• Effective cross-overs between atypicals

• High efficacy and rapid response onset

• Mild side effects

• Limited research

Novel Antipsychotics• Act on dopamine, serotonin,

glutamate and other receptors

• Beneficial effects on depressive symptoms

• 50% response

• 25% remission

• Direct effects vs. augmenting actions– More research is necessary

SSRIs

• Used first b/c high tolerability/ low toxicity

• No response from SSRI (or intolerable) -What’s the next step? Med switches Augmentation

Med Switches• 1 in 4 patients on SSRI’s have a

response on 2nd drug:– Bupropion-SR– Sertraline– Venlafaxine-XR

• Within class 1st SSRI may be ineffective/ intolerable 2nd SSRI may be effective/ tolerable• Out-of-class• Dual-action agent

Augmentation

• Sustained release bupropion group

• Buspirone group

Similar response and remission rates

BUT

Bupropion had greater symptom reduction and tolerability

1st Line Treatments?

• Skip 1st step of only SSRIs

• Augmentation or combination treatments 1st

• Faster and larger remission rates

Acknowledgements• Atiq, Rafay. “Treatment-Resistant Depression.” Hospital Physician.

Vol 10. Part 1. February 2006. pp. 2-11.

• Barbee, Conrad, Jamhour. “The effectiveness of Olanzapine, Risperidone, Quetiapine, and Ziprasidone as Augmentation Agents in Treatment Resistant Major Depressive Disorder.” Journal of Clinical Psychaitry. Vol 65. No 7. July 2004. pp.975-981.

• Rosack, Jim. “Companies Desperately Seek Antidepressant Breakthrough.” Psychiatric News. June 2, 2006. pp. 22-23.

• Rush, et. Al. “Buropion-SR, Sertralie, or Venlafaxine-XR after failure of SSRIs for depression.” New England Journal of Medicine. Vol 354, No 12. March 23, 2006. pp.1231-1242

Acknowledgments Cont.• Shelton, Richard. “Novel Antipsychotics for Treatment-Resistant

Depression”. Psychiatric Times. October 2004. pp.72-74.

• Trivedi, Souery, Papakostas. “Treatment- Resistant Depression.” Journal of Clinical Psychiatry. Vol 67. Supplement 6, 2006. pp.16-22.

• Trivedi, et.al. “Medicatio Augmentation after Failure of SSRIs for Depression.” New England Journal of Medicine. Vol 354. No 12. March 23, 2006. PP. 1243-1252.

• Valenstein, et.al. “What Happened to Lithium? Antidepressant Augmentation in Clinical Settings.” American Journal of Psychiatry. Vol 163. No 7. July 2006. pp.1219-1225.