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RESISTANT DEPRESSION
Presented By
Mostafa Mahmoud Elsabban
Resident of Psychiatry department
•Depression is ranked by the WHO
as the 2nd highest cause of
disability across the world.
•Projected to become the second
by 2020
[World Bank, 2010].
Epidemiology
COURSE
• ONSET.
• The first depressive episode occurs before age 40 years in about 50 percent of
patients.
• A family history of mood disorder is associated with a younger age at onset of
depression
(Nierenberg et al., 2007).
• DURATION.
• An untreated depressive episode lasts 6 to 12 months; most treated episodes
last about 3 months.
• The withdrawal of antidepressants before 3 months has elapsed almost always
results in the return of the symptoms.
• As the course of the disorder progresses, patients tend to have more frequent
episodes that last longer.
COURSE
• DEVELOPMENT OF MANIC EPISODES.
• About 5 to 10 percent of patients with an initial diagnosis of MDD have a manic
episode 6 to 10 years after the first depressive episode.
• Often occurs after two to four depressive episodes.
• when to suspect??
• Some clinicians report that the depression of patients who are later classified as
having bipolar I disorder is often characterized by
• hypersomnia,
• psychomotor retardation,
• a history of postpartum episodes,
• a family history of bipolar I disorder,
• a history of antidepressant-induced hypomania.
Resistant depression
Prognosis.
• MDD is not a benign disorder.
• It tends to be chronic, and patients tend to relapse.
• About 25 percent of patients experience a recurrence of major
depressive disorder in the first 6 months after release from a hospital,
• about 30 to 50 percent in the following 2 years, and
• about 50 to 75 percent in 5 years.
• The incidence of relapse is lower if patients continue prophylactic
treatment.
• Generally, as a patient experiences more and more depressive
episodes, the time between the episodes decreases, and the severity
of each episode increases
PROGNOSTIC INDICATORS
Good prognostic factors
• Mild episodes
• The absence of psychotic symptoms
• Short hospital stay
• stable family functioning
• Absence of a comorbid psychiatric disorder
• Good premorbid personality
• Negative family history
• Presence of stressors
PROGNOSTIC INDICATORS
Poor prognosis
• Sever episodes
• coexisting dysthymic disorder
• Abuse of alcohol and other substances,
• Anxiety disorder symptoms
• A history of more than one previous depressive episode.
• Men are more likely than women to experience a chronically
impaired course.
• Positive family history
• Poor social support
•Despite the recent advances in treatment of depression, only
30%–40% of patients achieve remission following initial
treatment.
•10-15% show partial response.
•20-35% are non-responsive.
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?
Operational definitions of treatment response
Remission >75%
Response 50% - 74%
Partial Response 25% - 49%
Nonresponse <25%
Operational definitions of treatment response
Terminology
• Non response :
no clinically meaningful response to treatment. (<20%)
• Partial response:
25-49% decrease in depression rating scale score.
Residual symptoms: irritability, deficits social functioning, dysfunctional
attitudes, depressive cognitions
• Treatment response :
>50% decrease in HAM-D score.
• Remission:
2 consecutive months of an asymptomatic stage (HAM-D ≤ 7).
• Recovery:
≥ 6 months of remission.
• There is no single accepted definition
• It is Poorly defined term.
• It may mean : failure to respond to a trial of more than one antidepressant drug
for duration of 6-8 wks.
• It may mean : unremitting depression despite treatment with at least 2 different
antidepressant trials
• It may mean : unremitting depression despite treatment with an antidepressant
trial & a course of ECT.
Definition of TREATMENT-RESISTANT
DEPRESSION (TRD)
Failure to respond to 2 adequate trials (adequate
dosage for adequate duration) of different
chemical classes.
DEFINITION OF TREATMENT-RESISTANT
DEPRESSION (TRD)
DEFINITION OF TREATMENT-RESISTANT
DEPRESSION (TRD)
• Although it appears simple, defining “inadequate response” and “adequate
antidepressant treatment” remains controversial
• Inadequate response typically means:
• failure to achieve remission; patients who improve but who fail to remit with
initial treatment are more likely to have a recurrence.
• (e.g., HAM-D < 7).
• Several researchers have suggested that functional recovery also needs to be
taken into consideration when defining adequate response.
• Adequate antidepressant treatment
• At least one trial with an antidepressant with established efficacy in MDD (with
sufficient duration and doses) is considered to be “adequate antidepressant
treatment.”
• However, defining sufficient duration and dose is difficult.
• Sufficient dose is either the minimum dosage that will produce the
expected effect or the maximum dosage that the patient can tolerate until the
expected effect is achieved.
• sufficient duration of an antidepressant is considered to be long enough to
produce a robust therapeutic effect.8 In clinical trials 4–6 weeks has been used
as the threshold for sufficient duration, but some researchers suggest using a
longer period, up to 8–12 weeks.
• In STAR*D, many patients who initially failed to achieve remission or response,
eventually achieved remission or a response by 14 weeks.
STAGING MODELS OF TREATMENT-RESISTANT
DEPRESSION
• Thase & Rush (1997) were the first to publish a comprehensive
staging model, taking into account the number and class of
treatments received in order to indicate the level of resistance.
• Lately, in response to the need to validate treatment strategies or
specific medications in TRD, regulatory authorities in Europe and
the USA have elaborated their own recommendations for use in
clinical trials such as
• European staging model (1999),
• Massachusetts general hospital staging model (2003) &
• Maudsley staging model (2009).
Thase and Rush stages
•In the staging models:
nonresponse to two agents of different classes has been
thought to be more difficult to treat than non-response to two
agents of the same class.
•In addition, there is an implicit hierarchy of antidepressant
treatments, with:
MAOIs being considered as superior to TCAs and SSRIs, and
TCAs being considered as more effective than SSRIs.
• These two concepts have never been fully investigated.
STAGE I FAILURE OF AT LEAST ONE ADEQUATE TRIAL OF ANTI DEPRESSANT MONOTHERAPY
STAGE II STAGE 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
• Greater number of somatic symptoms
• History of childhood emotional abuse and sequelae
Causes of Resistance
(Ds)
Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004
• 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
• Chronicity of depression (illness lasting 2 years or more)
Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004
Causes of Resistance
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.
Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004
Causes of Resistance
• 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
Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004
Pseudo resistance
Causes of Resistance
• Re-evaluation of patient history & presentation.
• Assessment of treatment adequacy:
• Dose
• Duration
• Drug compliance
• Drug- drug interactions
• Treatment strategies include
• Pharmacological - optimization, augmentation, combination, switching.
• Somatic treatments. – DBS, VNS, rTMS
• Non pharmacological.
Management
Duration of treatment
• 40% of people may relapse after an index depressive episode within 2 years,
and 60% within 5 years.
• They should therefore be taken for 6–9 months after recovery from a single
episode (to cover the assumed duration of most single untreated episodes
& minimises risk of relapse).
• In those patients who have had multiple episodes, there is evidence of
benefit from maintenance treatment for at least 2 years; no upper duration
of treatment has been identified.
Second episode:
• 1-2 years
Third or subsequent episode:
• 3-5 years or longer
Next step treatments
•Approximately a third of patients do not respond to
the first antidepressant that is prescribed.
Strategies for
Refractory Depression
• Switch to a different antidepressant (within class or across
class)
• Augment the treatment regimen with a non-antidepressant
agent
• Combine the initial antidepressant with a second
antidepressant
Papakostas G. J Clin Psychiatry. 2009;70(S6):16-25.
COMMON TREATMENT STRATEGIES FOR
TREATMENT-RESISTANT DEPRESSION
•The optimal method has not been determined.
•A retrospective analysis from Sequenced Treatment
Alternatives to Relieve Depression (STAR*D ) showed no
significant differences (in terms of remission rate,
response rate, time to remission, and time to response)
between switching and augmentation strategies.
Pharmacological Options After Failure of First
Antidepressant
• Optimize dose and address adherence
• Change to another antidepressant (Switch)
• Same class
• Different class
• Add a second antidepressant (Combine)
• Add a non-antidepressant (Augment)
• Lithium or other mood stabilizer
• Thyroid hormone
• Psychostimulant
• Atypical antipsychotic
• 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
Usual therapeutic doses for depression
SSRIs:
• Citalopram (Cipramil) 20-40mg
• Escitalopram (Cipralex) 10-20mg
• Fluoxetine (Prozac) 20-60mg
• fluvoxamine (Faverin) 150-300mg?
• Paroxetine (Seroxat) 20-60mg
• Sertraline (Lustral) 50-100mg
Tricyclics:
• Amitriptyline, clomipramine (Anafranil),
dothiepin, imipramine, nortriptyline –
• 125-150mg/d
Newer:
• Mirtazapine (Zispin) 15-45mg
• Venlafaxine (Efexor) 75-225mg
• Duloxetine (Cymbalta) 60-120mg
• Trazodone (Molipaxin) 150mg?
• Reboxetine (Edronax) 8-12mg
• 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
Resistant depression
• 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
• 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.
Combination therapy
Combining Two Antidepressants with Different
Mechanisms of Action
• Combining two antidepressants with different mechanisms of action is an
attractive approach for managing TRD.
• Combination of an SSRI or an SNRI with a norepinephrine-dopamine re-uptake
inhibitor(bupropion)or a serotonin-norepinephrine antagonist (mirtazapine or
mianserin) is a commonly used combination, with expected synergistic effects of
their pharmacodynamic properties.
• One RCT of mirtazapine in combination with fluoxetine, venlafaxine, or
bupropion compared with fluoxetine monotherapy and found that combination
therapies were associated with
approximately twice the remission rate of fluoxetine monotherapy.
•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.
Augmentation strategies
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.
•Buspirone
Augmentation strategies
• Olanzapine, Quetiapine (300-600mg/day) and to some extent aripiprazole (5-
20mg/day) have good supportive data from controlled clinical trials as
augmenters of SSRIs
e.g. Olanzapin Flouxetien combination (OFC).
• Data for risperidone (0.5-2 mg/day) are not robust, but can be used as an
augmenting agent.
• Newer atypical antipsychotics as ziprasidone, paliperidone, asenapine, and
iloperidone, have not been examined for their efficacy in controlled trials.
• Use of Clozapine is limited due to its adverse effect profile, but can be used as
last resort after other Aps fail
Atypical antispychotics
• 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
Other augmentation approaches
Novel Therapeutic Agents
• New drugs with mechanisms that fall outside of those associated with the classical monoamine
receptor hypothesis of depression offer great promise for the treatment of TRD.
1- Ketamine, a NMDA receptor antagonist:
• Has shown rapid antidepressant effects.
• Recently, several open-label studies with repeated intravenous ketamine infusions have shown
promising results.
• Increases BDNF concentration
• Through these mechanisms it causes enhanced synaptic plasticity
2- Anti-inflammatory agents:
• Inflammation is thought to be associated with treatment response in depression. In this context, anti-
inflammatory agents may be effective.
• Aspirin, celecoxib, infliximab, N-acetylcysteine have all been studied; however, no
definite answer has been reached about their benefits.
3- Dopamine Agonists
• 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.
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,
4- S-adenosyl metheonine
• 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.
Seo RJ et al.,Atypical Antipsychotics and Other Therapeutic Options for Treatment
of Resistant Major Depressive Disorder.; Pharmaceuticals 2010, 3, 3522-3542
5- Melatonin Receptor Agonists
• Agomelatine
• Agonist at MT1 & MT2.. Antagonist at 5HT2C
• Given 25mg/day in HS dosage.
Augmentation
Non-pharmacological Interventions
1- psychotherapy:
• Adjunctive psychotherapy can be helpful in TRD.
• In the STAR*D study, cognitive therapy was included in Level 2.
• No significant difference was observed in remission rates between the cognitive
therapy group and the medication-only group.
• A randomized trial investigating the effects of cognitive behavioral therapy (CBT)
in women with TRD (n = 469), adding CBT to usual care, significantly increased
treatment response.
• However, the efficacy of other types of psychotherapy has not been investigated
in TRD.
Augmentation
• Brain stimulation focuses on the direct or indirect alteration of brain function by electrical or magnetic
methods.
2- Electroconvulsive therapy (ECT):
• The oldest brain stimulation methods, has long been viewed as an effective treatment for severe
depression.
• Cognitive impairment is its most common side effect.
3- Vagus nerve stimulation (VNS) therapy:
• Stimulates the left vagus nerve repetitively using small electrical pulse from an neuro-stimulator
implanted on patients’ neck.
• In an open study with patients afflicted with chronic MDD who had failed to respond to more than four
adequate antidepressant treatments, the response rate to VNS was approximately 30%.
• Recently, it has been approved as an adjunctive treatment for TRD in the US.
• Side effects (such as voice alteration, dyspnea, and neck pain) of VNS are generally mild.
• However, it requires an invasive procedure, and most of the studies done so far had relatively small
sample sizes.
Augmentation
4- Deep brain stimulation (DBS):
• Was initially developed for the treatment of Parkinson’s disease.
• DBS therapy stimulates targeted brain region via electrodes which are permanently
implanted.
• Subcallosal cingulate white matter, the ventral caudate, the ventral striatum, and
the subcallosal cingulate white matter are commonly targeted.
• Several small open studies have shown promise.
5- Psychosurgery:
• In severe TRD, psychosurgery also has been tried.
• Subcaudate tractomy, anterior cingulatomy, limbic leucotomy, and anterior
capsulotomy are the most common methods.
• Its efficacy has been established, but its use is still limited.
• 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
CONCLUSIONS
• TRD is common, although its definition is not exactly clear.
• Since some cases of TRD could actually be pseudo-resistance or non-response
due to suboptimal treatment, clinicians should re-do diagnostic evaluations and
check patients’ drug compliance when remission does not develop.
• Optimal treatment strategies for TRD are not well established.
• Identifying mechanisms and predicting factors of poor response to
antidepressants will be important.
THANK YOU

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Resistant depression

  • 1. RESISTANT DEPRESSION Presented By Mostafa Mahmoud Elsabban Resident of Psychiatry department
  • 2. •Depression is ranked by the WHO as the 2nd highest cause of disability across the world. •Projected to become the second by 2020 [World Bank, 2010]. Epidemiology
  • 3. COURSE • ONSET. • The first depressive episode occurs before age 40 years in about 50 percent of patients. • A family history of mood disorder is associated with a younger age at onset of depression (Nierenberg et al., 2007). • DURATION. • An untreated depressive episode lasts 6 to 12 months; most treated episodes last about 3 months. • The withdrawal of antidepressants before 3 months has elapsed almost always results in the return of the symptoms. • As the course of the disorder progresses, patients tend to have more frequent episodes that last longer.
  • 4. COURSE • DEVELOPMENT OF MANIC EPISODES. • About 5 to 10 percent of patients with an initial diagnosis of MDD have a manic episode 6 to 10 years after the first depressive episode. • Often occurs after two to four depressive episodes. • when to suspect?? • Some clinicians report that the depression of patients who are later classified as having bipolar I disorder is often characterized by • hypersomnia, • psychomotor retardation, • a history of postpartum episodes, • a family history of bipolar I disorder, • a history of antidepressant-induced hypomania.
  • 6. Prognosis. • MDD is not a benign disorder. • It tends to be chronic, and patients tend to relapse. • About 25 percent of patients experience a recurrence of major depressive disorder in the first 6 months after release from a hospital, • about 30 to 50 percent in the following 2 years, and • about 50 to 75 percent in 5 years. • The incidence of relapse is lower if patients continue prophylactic treatment. • Generally, as a patient experiences more and more depressive episodes, the time between the episodes decreases, and the severity of each episode increases
  • 7. PROGNOSTIC INDICATORS Good prognostic factors • Mild episodes • The absence of psychotic symptoms • Short hospital stay • stable family functioning • Absence of a comorbid psychiatric disorder • Good premorbid personality • Negative family history • Presence of stressors
  • 8. PROGNOSTIC INDICATORS Poor prognosis • Sever episodes • coexisting dysthymic disorder • Abuse of alcohol and other substances, • Anxiety disorder symptoms • A history of more than one previous depressive episode. • Men are more likely than women to experience a chronically impaired course. • Positive family history • Poor social support
  • 9. •Despite the recent advances in treatment of depression, only 30%–40% of patients achieve remission following initial treatment. •10-15% show partial response. •20-35% are non-responsive. Rates of Response
  • 10. • 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?
  • 11. Operational definitions of treatment response
  • 12. Remission >75% Response 50% - 74% Partial Response 25% - 49% Nonresponse <25% Operational definitions of treatment response
  • 13. Terminology • Non response : no clinically meaningful response to treatment. (<20%) • Partial response: 25-49% decrease in depression rating scale score. Residual symptoms: irritability, deficits social functioning, dysfunctional attitudes, depressive cognitions • Treatment response : >50% decrease in HAM-D score. • Remission: 2 consecutive months of an asymptomatic stage (HAM-D ≤ 7). • Recovery: ≥ 6 months of remission.
  • 14. • There is no single accepted definition • It is Poorly defined term. • It may mean : failure to respond to a trial of more than one antidepressant drug for duration of 6-8 wks. • It may mean : unremitting depression despite treatment with at least 2 different antidepressant trials • It may mean : unremitting depression despite treatment with an antidepressant trial & a course of ECT. Definition of TREATMENT-RESISTANT DEPRESSION (TRD)
  • 15. Failure to respond to 2 adequate trials (adequate dosage for adequate duration) of different chemical classes. DEFINITION OF TREATMENT-RESISTANT DEPRESSION (TRD)
  • 16. DEFINITION OF TREATMENT-RESISTANT DEPRESSION (TRD) • Although it appears simple, defining “inadequate response” and “adequate antidepressant treatment” remains controversial • Inadequate response typically means: • failure to achieve remission; patients who improve but who fail to remit with initial treatment are more likely to have a recurrence. • (e.g., HAM-D < 7). • Several researchers have suggested that functional recovery also needs to be taken into consideration when defining adequate response.
  • 17. • Adequate antidepressant treatment • At least one trial with an antidepressant with established efficacy in MDD (with sufficient duration and doses) is considered to be “adequate antidepressant treatment.” • However, defining sufficient duration and dose is difficult. • Sufficient dose is either the minimum dosage that will produce the expected effect or the maximum dosage that the patient can tolerate until the expected effect is achieved. • sufficient duration of an antidepressant is considered to be long enough to produce a robust therapeutic effect.8 In clinical trials 4–6 weeks has been used as the threshold for sufficient duration, but some researchers suggest using a longer period, up to 8–12 weeks. • In STAR*D, many patients who initially failed to achieve remission or response, eventually achieved remission or a response by 14 weeks.
  • 18. STAGING MODELS OF TREATMENT-RESISTANT DEPRESSION • Thase & Rush (1997) were the first to publish a comprehensive staging model, taking into account the number and class of treatments received in order to indicate the level of resistance. • Lately, in response to the need to validate treatment strategies or specific medications in TRD, regulatory authorities in Europe and the USA have elaborated their own recommendations for use in clinical trials such as • European staging model (1999), • Massachusetts general hospital staging model (2003) & • Maudsley staging model (2009).
  • 19. Thase and Rush stages •In the staging models: nonresponse to two agents of different classes has been thought to be more difficult to treat than non-response to two agents of the same class.
  • 20. •In addition, there is an implicit hierarchy of antidepressant treatments, with: MAOIs being considered as superior to TCAs and SSRIs, and TCAs being considered as more effective than SSRIs. • These two concepts have never been fully investigated.
  • 21. STAGE I FAILURE OF AT LEAST ONE ADEQUATE TRIAL OF ANTI DEPRESSANT MONOTHERAPY STAGE II STAGE 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
  • 22. • 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 • Greater number of somatic symptoms • History of childhood emotional abuse and sequelae Causes of Resistance (Ds) Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004
  • 23. • 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 • Chronicity of depression (illness lasting 2 years or more) Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004 Causes of Resistance
  • 24. 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. Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004 Causes of Resistance
  • 25. • 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 Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004 Pseudo resistance Causes of Resistance
  • 26. • Re-evaluation of patient history & presentation. • Assessment of treatment adequacy: • Dose • Duration • Drug compliance • Drug- drug interactions • Treatment strategies include • Pharmacological - optimization, augmentation, combination, switching. • Somatic treatments. – DBS, VNS, rTMS • Non pharmacological. Management
  • 27. Duration of treatment • 40% of people may relapse after an index depressive episode within 2 years, and 60% within 5 years. • They should therefore be taken for 6–9 months after recovery from a single episode (to cover the assumed duration of most single untreated episodes & minimises risk of relapse). • In those patients who have had multiple episodes, there is evidence of benefit from maintenance treatment for at least 2 years; no upper duration of treatment has been identified. Second episode: • 1-2 years Third or subsequent episode: • 3-5 years or longer
  • 28. Next step treatments •Approximately a third of patients do not respond to the first antidepressant that is prescribed.
  • 29. Strategies for Refractory Depression • Switch to a different antidepressant (within class or across class) • Augment the treatment regimen with a non-antidepressant agent • Combine the initial antidepressant with a second antidepressant Papakostas G. J Clin Psychiatry. 2009;70(S6):16-25.
  • 30. COMMON TREATMENT STRATEGIES FOR TREATMENT-RESISTANT DEPRESSION •The optimal method has not been determined. •A retrospective analysis from Sequenced Treatment Alternatives to Relieve Depression (STAR*D ) showed no significant differences (in terms of remission rate, response rate, time to remission, and time to response) between switching and augmentation strategies.
  • 31. Pharmacological Options After Failure of First Antidepressant • Optimize dose and address adherence • Change to another antidepressant (Switch) • Same class • Different class • Add a second antidepressant (Combine) • Add a non-antidepressant (Augment) • Lithium or other mood stabilizer • Thyroid hormone • Psychostimulant • Atypical antipsychotic
  • 32. • 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
  • 33. Usual therapeutic doses for depression SSRIs: • Citalopram (Cipramil) 20-40mg • Escitalopram (Cipralex) 10-20mg • Fluoxetine (Prozac) 20-60mg • fluvoxamine (Faverin) 150-300mg? • Paroxetine (Seroxat) 20-60mg • Sertraline (Lustral) 50-100mg Tricyclics: • Amitriptyline, clomipramine (Anafranil), dothiepin, imipramine, nortriptyline – • 125-150mg/d Newer: • Mirtazapine (Zispin) 15-45mg • Venlafaxine (Efexor) 75-225mg • Duloxetine (Cymbalta) 60-120mg • Trazodone (Molipaxin) 150mg? • Reboxetine (Edronax) 8-12mg
  • 34. • 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)
  • 35. • 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
  • 36. Al-Harbi ., Treatment-resistant depression: therapeutic trends, challenges, and future directions.; Patient Preference and Adherence 2012:6 ,369–388
  • 38. • 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
  • 39. • 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. Combination therapy
  • 40. Combining Two Antidepressants with Different Mechanisms of Action • Combining two antidepressants with different mechanisms of action is an attractive approach for managing TRD. • Combination of an SSRI or an SNRI with a norepinephrine-dopamine re-uptake inhibitor(bupropion)or a serotonin-norepinephrine antagonist (mirtazapine or mianserin) is a commonly used combination, with expected synergistic effects of their pharmacodynamic properties. • One RCT of mirtazapine in combination with fluoxetine, venlafaxine, or bupropion compared with fluoxetine monotherapy and found that combination therapies were associated with approximately twice the remission rate of fluoxetine monotherapy.
  • 41. •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
  • 42. •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. Augmentation strategies Philip et al.,Pharmacologic Approaches to Treatment Resistant Depression: A Re-examination for the Modern Era; Expert Opin Pharmacother. 2010 April ; 11(5)
  • 43. •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. •Buspirone Augmentation strategies
  • 44. • Olanzapine, Quetiapine (300-600mg/day) and to some extent aripiprazole (5- 20mg/day) have good supportive data from controlled clinical trials as augmenters of SSRIs e.g. Olanzapin Flouxetien combination (OFC). • Data for risperidone (0.5-2 mg/day) are not robust, but can be used as an augmenting agent. • Newer atypical antipsychotics as ziprasidone, paliperidone, asenapine, and iloperidone, have not been examined for their efficacy in controlled trials. • Use of Clozapine is limited due to its adverse effect profile, but can be used as last resort after other Aps fail Atypical antispychotics
  • 45. • 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
  • 47. Other augmentation approaches Novel Therapeutic Agents • New drugs with mechanisms that fall outside of those associated with the classical monoamine receptor hypothesis of depression offer great promise for the treatment of TRD. 1- Ketamine, a NMDA receptor antagonist: • Has shown rapid antidepressant effects. • Recently, several open-label studies with repeated intravenous ketamine infusions have shown promising results. • Increases BDNF concentration • Through these mechanisms it causes enhanced synaptic plasticity 2- Anti-inflammatory agents: • Inflammation is thought to be associated with treatment response in depression. In this context, anti- inflammatory agents may be effective. • Aspirin, celecoxib, infliximab, N-acetylcysteine have all been studied; however, no definite answer has been reached about their benefits.
  • 48. 3- Dopamine Agonists • 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. 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,
  • 49. 4- S-adenosyl metheonine • 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. Seo RJ et al.,Atypical Antipsychotics and Other Therapeutic Options for Treatment of Resistant Major Depressive Disorder.; Pharmaceuticals 2010, 3, 3522-3542
  • 50. 5- Melatonin Receptor Agonists • Agomelatine • Agonist at MT1 & MT2.. Antagonist at 5HT2C • Given 25mg/day in HS dosage.
  • 51. Augmentation Non-pharmacological Interventions 1- psychotherapy: • Adjunctive psychotherapy can be helpful in TRD. • In the STAR*D study, cognitive therapy was included in Level 2. • No significant difference was observed in remission rates between the cognitive therapy group and the medication-only group. • A randomized trial investigating the effects of cognitive behavioral therapy (CBT) in women with TRD (n = 469), adding CBT to usual care, significantly increased treatment response. • However, the efficacy of other types of psychotherapy has not been investigated in TRD.
  • 52. Augmentation • Brain stimulation focuses on the direct or indirect alteration of brain function by electrical or magnetic methods. 2- Electroconvulsive therapy (ECT): • The oldest brain stimulation methods, has long been viewed as an effective treatment for severe depression. • Cognitive impairment is its most common side effect. 3- Vagus nerve stimulation (VNS) therapy: • Stimulates the left vagus nerve repetitively using small electrical pulse from an neuro-stimulator implanted on patients’ neck. • In an open study with patients afflicted with chronic MDD who had failed to respond to more than four adequate antidepressant treatments, the response rate to VNS was approximately 30%. • Recently, it has been approved as an adjunctive treatment for TRD in the US. • Side effects (such as voice alteration, dyspnea, and neck pain) of VNS are generally mild. • However, it requires an invasive procedure, and most of the studies done so far had relatively small sample sizes.
  • 53. Augmentation 4- Deep brain stimulation (DBS): • Was initially developed for the treatment of Parkinson’s disease. • DBS therapy stimulates targeted brain region via electrodes which are permanently implanted. • Subcallosal cingulate white matter, the ventral caudate, the ventral striatum, and the subcallosal cingulate white matter are commonly targeted. • Several small open studies have shown promise. 5- Psychosurgery: • In severe TRD, psychosurgery also has been tried. • Subcaudate tractomy, anterior cingulatomy, limbic leucotomy, and anterior capsulotomy are the most common methods. • Its efficacy has been established, but its use is still limited.
  • 54. • 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.
  • 55. • 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
  • 56. • 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
  • 57. • 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):
  • 58. • 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
  • 59. CONCLUSIONS • TRD is common, although its definition is not exactly clear. • Since some cases of TRD could actually be pseudo-resistance or non-response due to suboptimal treatment, clinicians should re-do diagnostic evaluations and check patients’ drug compliance when remission does not develop. • Optimal treatment strategies for TRD are not well established. • Identifying mechanisms and predicting factors of poor response to antidepressants will be important.