Transcript Treatment Resistant Depression

Treatment Resistant
Depression
Anita S. Kablinger, M.D.
Associate Professor
Departments 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 NonResponse
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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 nonmelancholic 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 Guidelines
Committee 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
Studies
More 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
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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
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1
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.1622.
• 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.