treatment resistant depression anita s. kablinger, m.d. associate professor departments of...
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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
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.