This document discusses treatment resistant depression. It begins by providing epidemiological data on depression worldwide and notes that treatment resistant depression (TRD) is becoming more prevalent. It then discusses factors associated with TRD like psychiatric and medical comorbidities, gender, family history, illness severity and chronicity. The document outlines approaches to defining and staging TRD. It discusses challenges in differentiating true treatment resistance from pseudo-resistance. Finally, it summarizes large clinical trials on sequencing treatments for TRD like the STAR*D trial.

1. TREATMENT RESISTANT
DEPRESSION

2. INTRODUCTION
• DEPRESSIVE DISORDERS ARE A LEADING CAUSE OF
DISABILITY WORLDWIDE.
• THE LIFETIME PREVALENCE RATES OF UNIPOLAR
DEPRESSION (UPD) IN MALES AND FEMALES OF
FIRST-WORLD COUNTRIES ARE APPROXIMATELY
15 AND 25 PERCENT, RESPECTIVELY. THE FIGURES
APPEAR TO BE EQUALLY DISHEARTENING IN
DEVELOPING COUNTRIES.
• BY THE YEAR 2020, UNIPOLAR DEPRESSION IS
PROJECTED TO BE THE SECOND LEADING CAUSE
OF DISABILITY ADJUSTED LIFE YEARS ( DALYS) ALL
OVER THE WORLD.

3. EPIDEMIOLOGY
• THE HIGHEST RATES OF DEPRESSION OCCUR IN
INDIVIDUALS BETWEEN THE AGES OF 25 AND 44
YEARS.
• FEMALES ARE ALMOST TWICE AS LIKELY ( 10%-
25%) AS MALES(5%- 12%) TO EXPERIENCE
DEPRESSION

4. CONTD…
• UNTREATED DEPRESSION HAS SIGNIFICANT
ECONOMIC, SOCIAL, PHYSICAL AND
PSYCHOLOGICAL CONSEQUENCES.
• FACTORS CONTRIBUTING TO ECONOMIC BURDEN
OF DEPRESSION INCLUDES
– PREVALENCE OF THE DISEASE
– TREATMENT RATE
– RATE AND DEGREE OF IMPAIRMENT.(REDUCED PRODUCTIVITY
AND INCREASED ABSENTEEISM)
– HIGHER RATES OF PREMATURE DEATH RELATED TO
CARDIOVASCULAR DISEASE AND MYOCARDIAL INFARCTION
– 15% OF PEOPLE DIAGNOSED WITH MDD WILL COMMIT
SUICIDE, AND TWO THIRDS OF ALL SUICIDES ARE RELATED TO
DEPRESSION(AJP 2000)

5. PREVALENCE OF TREATMENT
RESISTANT DEPRESSION
• PREVALENCE ESTIMATES FOR TRD ARE AVAILABLE
FROM SEVERAL SOURCES, INCLUDING LARGE
CLINICAL TRIALS LARGE META-ANALYSES, OR
NATURALISTIC STUDIES.
• FOR EXAMPLE, IN THE FIRST LEVEL OF THE
SEQUENCED TREATMENT ALTERNATIVES TO
RELIEVE DEPRESSION (STAR*D) TRIAL, ONLY ABOUT
30% OF PATIENTS WERE IN REMISSION
FOLLOWING UP TO 12 WEEKS OF THERAPY WITH
THE SELECTIVE SEROTONIN RECEPTOR INHIBITOR
(SSRI) CITALOPRAM.
– IN ADDITION, 15.8% OF PATIENTS DEVELOPED AN
INTOLERABLE ADVERSE EVENT, 38.6% MODERATE-TO-
SEVERE IMPAIRMENT DUE TO AN ADVERSE EVENT,
– 8.6% DISCONTINUED TREATMENT DUE TO ADVERSE
EVENTS
– 4% DEVELOPED A SERIOUS ADVERSE EVENT

6. DEFINITION OF TREATMENT
RESISTANT DEPRESSION (TRD)
• WHILE THERE IS NO CONSENSUS ON THE DEFINITION OF
TREATMENT RESISTANT DEPRESSION (TRD), CERTAIN
GUIDELINES BASED ON ACCEPTED CLINICAL OUTCOMES
MEASURES, SUCH AS THE HAMILTON RATING SCALE FOR
DEPRESSION (HAM-D), CAN BE USED TO IDENTIFY TRD.
• NIERENBERG AND DECECCO SUGGESTED THAT TRD IN
PATIENTS WHO RECEIVED ADEQUATE TREATMENT
COULD BE DEFINED BASED ON ANY OF 3 CRITERIA:
– FAILURE TO ACHIEVE A MINIMUM RESPONSE (E.G., LESS THAN A
25% DECREASE FROM BASELINE HAM-D SCORE)
– FAILURE TO ACHIEVE A RESPONSE (E.G., LESS THAN A
50%DECREASE FROM BASELINE HAM-D SCORE),
– OR FAILURE TO ACHIEVE REMISSION (E.G., A FINAL HAM-D SCORE
OF AT LEAST 7)

7. WHY ACHIEVING
REMISSION IS IMPORTANT
• PATIENTS WHO ARE TREATMENT RESISTANT USE A
DISPROPORTIONATELY LARGER SHARE OF HEALTH CARE
RESOURCES, HAVE SIGNIFICANTLY MORE CLAIMS FOR
COMORBID CONDITIONS, AND COST EMPLOYERS MORE
IN LOST PRODUCTIVITY COMPARED WITH PATIENTS
WITH MAJOR DEPRESSION WHO RESPOND TO
TREATMENT.
• RESIDUAL SYMPTOMS CARRY A 3 TIMES RATE OF
RELAPSE (76% VS 25%) (PAYKEL ET AL, 1995)
• RESIDUAL SYMPTOMS ARE ASSOCIATED WITH EARLY
EPISODE OF RELAPSE AND ARE A STRONGER PREDICTOR
OF RELAPSE THAN A HISTORY OF MDE ( JUDD 1998)

8. NEUROBIOLOGY OF DEPRESSION
Schematic connections between
the pre-frontal cortex and limbic
structures within the limbic-
cortico-striato-pallido-thalamic
circuits related to the medial and
orbital prefrontal cortex networks
implicated in depression.

9. • A DECREASE IN THE INHIBITORY CONTROL OF THE
LIMBIC STRUCTURES BY THE PFC IS ASSOCIATED
WITH
– COGNITIVE
– BEHAVIOURAL
– OTHER SIGNS OF DEPRESSION
– ABNORMALITIES IN NEUROENDOCRINE FUNCTION
– PAIN MODULATION AND NEUROTRANSMITTER ACTIVITY
(AFFECTING THE RAPHE, SEROTONERGIC NUCLEI AND NA-
ERGIC NUCLEUS COERULEUS)
THROUGH ITS CONNECTIONS WITH THE
HYPOTHALAMUS AND THE MIDBRAIN, IN PARTICULAR
THE PERIAQUEDUCTAL AREA.

10. FUNCTIONAL AND STRUCTURAL
CHANGES IN THE LIMBIC AND PFC AREAS
IMPLICATED IN DEPRESSION
SUBSTRATE VOLUME
HISTOLOGI
CAL
CHANGES
METABOLIC
ACTIVITY
ANTIDEPRE
SSANT
EFFECTS
ORBITAL/V
MPFC
↓ ↓ ↑
ANTERIOR
CINGULATE
CORTEX
↓
↓
METABOLIC
ACTIVITY
HIPPOCAM
PUS
↓ ↓ ↑ VOLUME
AMYGDALA ↓
↓
METABOLIC
ACTIVITY
DLPFC ↓ ↓ ↓

11. NEUROCHEMICALS IN
DEPRESSION
Substrate Concentration/activity
Cortisol, CRH ↑
Proinflammatory cytokines ↑
BDNF ↓
5-HT neurotransmission ↓
NA neurotransmission ↓

12. PHASES OF TREATMENT

13. WHEN DO WE CHARACTERIZE A
RESPONSE AS TREATMENT RESISTANT?
• AFTER A PATIENT HAS BEEN ON AN ANTIDEPRESSANT AT FOR
A REASONABLE AMOUNT OF TIME AT AN ADEQUATE DOSE.
• NO COMMONLY ACCEPTED TIME POINT.
• MOST DRUG TRIAL DATA COMES FROM 8 WEEK LONG
STUDIES
• IF NO ONSET OF RESPONSE BY WEEKS 4 OR 6, THERE IS A 73-
88% CHANCE OF NOT HAVING ONSET OF RESPONSE BY END
OF 8 WEEK TRIAL ( NIERENBERG ET AL,2000), SO 4 WEEKS IS A
REASONABLE POINT TO INCREASE DOSE.
• AN 8- 12 WEEK COURSE IS CONSISTENT WITH ACUTE
TREATMENT FRAMEWORK AND ALLOWS PATIENTS 8 WEEKS
AT A DOSE EXPECTED TO PRODUCE RESPONSE
• NO COMMONLY ACCEPTED DETERMINATION OF ACCEPTED
DOSE
– RANGE FROM MINIMAL( E.G. 20 MG FLUOXETINE) TO
MODERATE DOSE ( E.G. 60 MG FLUOXETINE)
• MOST CLINICIANS CONSIDER MIDDLE RANGE DOSES TO BE
ADEQUATE

14. TREATMENT RESISTANCE VS
PSEUDORESISTANCE
• THE FIRST TASK OF THE CLINICIAN BEFORE
LABELLING A PATIENT AS TRD IS DIFFERENTIATING
BETWEEN TRUE TREATMENT RESISTANT
DEPRESSION FROM PSEUDO RESISTANCE.
• PROCESS OF RULING OUT PSEUDO RESISTANCE
FALLS INTO 3 AREAS IN THE CLINICAL ASSESSMENT:
– PHYSICIAN FACTOR
– PATIENT FACTORS
– ACCURACY OF DIAGNOSIS

15. FEATURES ASSOCIATED WITH
TREATMENT RESISTANT DEPRESSION
INCORRECT PRIMARY DIAGNOSIS
• IS THERE A PRIMARY DISORDER LIKE (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 DISORDER

16. CONTD.
• COMORBID PSYCHIATRIC DISORDERS
– ANXIETY DISORDERS
• COMMONLY CO-EXISTS 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
• DEPRESSIVE SEVERITY
• CHRONICITY OF DEPRESSION (ILLNESS
LASTING 2 YEARS OR MORE)

17. CONTD…
• PATIENTS’ FACTORS
– COMPLIANCE
– UNUSUAL PHARMACOKINETICS
• PHYSICIAN FACTORS
– UNDERDOSING
– INADEQUATE LENGTH OF TREATMENT

18. CONTD….
• CAREFUL EVALUATION FOR THE PRESENCE OF
UNRECOGNIZED DEPRESSIVE SUBTYPES-
– PSYCHOTIC DEPRESSION- UNRESPONSIVE TO
ANTIDEPRESSANTS ALONE.
– BIPOLAR DISORDER- NEEDS MOOD STABILIZER
– ATYPICAL DEPRESSION- BETTER RESPONSE TO
MOAI
– SEASONAL AFFECTIVE DISORDER- POORER
RESPONSE TO TCAS
– PREMENSTRUAL DYSPHORIC DISORDER-
SEROTONERGIC ANTIDEPRESSANTS WORK
BETTER.

19. FACTORS ASSOCIATED WITH
TREATMENT RESISTANCE
• PSYCHIATRIC CO- MORBIDITY
• MEDICAL CO- MORBID ILLNESS
• GENDER
• FAMILY HISTORY
• AGE OF ONSET
• ILLNESS SEVERITY
• CHRONICITY

20. PSYCHIATRIC CO- MORBIDITY
• KEITNER AND COLLEAGUES - 53% OF PATIENTS
ADMITTED WITH MAJOR DEPRESSION HAVE
COEXISTING AXIS I, II, OR III CONDITIONS. THEY
TERMED IT “COMPOUND DEPRESSION”
• ANXIETY DISORDERS.
• SUBSTANCE ABUSE- COLLATERAL HISTORY FOR
SUBSTANCES OF ABUSE ARE IMPORTANT IN THE
EVALUATION.
• PERSONALITY DISORDERS: OBSESSIVE
COMPULSIVE DISORDER(OCD)
• EATING DISORDERS
• BODY DYSMORPHIC DISORDER(BDD)
• MEDICATIONS-
- GLUCOCORTICOIDS
- ANTIHYPERTENSIVES

21. MEDICAL CONDITIONS THAT
CAN CAUSE DEPRESSION
• TUMORS: EITHER PRIMARY OR METASTATIC TO BRAIN,
ESPECIALLY LUNG CANCER AND PANCREATIC CANCER;
PARANEOPLASTIC SYNDROME
• INFECTIONS: CNS SYPHILIS, CNS HIV, MENINGITIS; UTI,
PNEUMONIA, MONONUCLEOSIS
• ENDOCRINE DISORDERS: CUSHING’S SYNDROME, HYPER OR
HYPOTHYROIDISM, ADDISON’S DISEASE,
HYPERPARATHYROIDISM
• HEMATOLOGICAL: ANEMIA, LEUKEMIA
• NEUROLOGICAL: HUNTINGTON’S DISEASE, PARKINSON’S
DISEASE, VARIOUS FORMS OF DEMENTIA, STROKE, BASAL
GANGLIA DEGENERATION, TRAUMATIC BRAIN INJURY
• TOXIC: ILLICIT DRUGS, ALCOHOL; MEDICATION SIDE EFFECTS
• NUTRITION AND ELECTROLYTES: VITAMIN DEFICIENCIES ( E.G..
NIACIN IN PELLAGRA), HYPONATREMIA, HYPOCALCEMIA
• OTHER: POST- MYOCARDIAL INFARCTION, RENAL FAILURE,
SLEEP APNEA.

22. GENDER
• FEMALE GENDER IS SAID TO BE MORE VULNERABLE
DUE TO GREATER PREVALENCE OF DEPRESSION IN
WOMEN ( KESSLER RC ET AL)
• WOMEN MAY BE LESS RESPONSIVE THAN MEN TO
TRICYCLICS.
• WOMEN RESPOND SIGNIFICANTLY BETTER TO
SERTRALINE THAN TO IMIPRAMINE
• MEN RESPONDED SIGNIFICANTLY BETTER TO
IMIPRAMINE
• PREMENOPAUSAL WOMEN RESPONDED BETTER TO
SERTRALINE, BUT THERE WAS NO DIFFERENCE IN
RESPONSE TO THE TWO DRUGS IN POST
MENOPAUSAL WOMEN (KORNSTEIN SG, SCHATZBERG
AF ET AL)

23. FAMILY HISTORY
• THERE ARE STUDIES SHOWING THAT A POSITIVE
FAMILY HISTORY IS ASSOCIATED WITH
– EARLY ONSET OF DEPRESSION
– CHRONICITY
• BOTH HAVE BEEN LINKED TO TREATMENT
RESISTANCE ( Klein dn, schatzberg af, mccullough
jp, et al)
• AGE OF ONSET- EXTREMES OF AGE.
– EARLY AGE OF ONSET- COMORBID PERSONALITY
DISORDERS SUBSTANCE ABUSE AND GREATER
FAMILY HISTORY OF MOOD DISORDERS.
– LATE ONSET- COMORBID MEDICAL ILLNESS,
PSYCHOTIC DEPRESSION, DEMENTIA, ORGANIC
MOOD DISORDER, SENSITIVITY TO S.E. OR LONGER
TIME TO RESPOND THUS BEING DECLARED
PREMATURELY.

24. GUIDELINE ON CLINICAL INVESTIGATION OF
MEDICINAL PRODUCTS IN THE TREATMENT OF
DEPRESSION (CPMP GUIDELINES)
• IN A CLINICAL PRAGMATIC VIEW A PATIENT HAS BEEN
CONSIDERED SUFFERING FROM TRD WHEN CONSECUTIVE
TREATMENT WITH TWO PRODUCTS OF DIFFERENT
PHARMACOLOGICAL CLASSES, USED FOR A SUFFICIENT
LENGTH OF TIME AT AN ADEQUATE DOSE, FAIL TO INDUCE A
CLINICALLY MEANINGFUL EFFECT (NON-RESPONSE).
• THIS APPROACH ASSUMES THAT NON-RESPONSE TO TWO
COMPOUNDS WITH DISTINCT MECHANISM OF ACTION (E.G.
ONE TRICYCLIC AND ONE SSRI) IS MORE DIFFICULT TO TREAT
THAN NON-RESPONSE TO TWO COMPOUNDS WITH THE SAME
MECHANISM OF ACTION (E.G. TWO SSRI’S);
• MOREOVER IT ASSUMES THAT THE SWITCH OF TREATMENT
WITHIN ONE CLASS IS LESS EFFECTIVE THAN THE SWITCH TO A
DIFFERENT PHARMACOLOGIC CLASS.

25. THASE-RUSH TREATMENT-RESISTANT
DEPRESSION (TRD) STAGING METHOD
TRD STAGE CRITERIA
STAGE 1 FAILURE OF AN ADEQUATE TRIAL OF 1 CLASS
OF MAJOR
ANTIDEPRESSANT
STAGE 2 FAILURE OF ADEQUATE TRIALS OF 2
DISTINCTLY DIFFERENT CLASSES OF
ANTIDEPRESSANTS
STAGE 3 STAGE 2 PLUS FAILURE OF A THIRD CLASS OF
ANTIDEPRESSANT, INCLUDING A TRICYCLIC
ANTIDEPRESSANT
STAGE 4 STAGE 3 PLUS FAILURE OF AN ADEQUATE
TRIAL OF A
MONOAMINE OXIDASE INHIBITOR
STAGE 5 STAGE 4 PLUS FAILURE OF AN ADEQUATE
COURSE OF
ELECTROCONVULSIVE THERAPY

26. SEQUENCED TREATMENT ALTERNATIVE
FOR TREATMENT OF DEPRESSION
• THE OVERALL GOAL OF THE STAR*D TRIAL WAS TO
ASSESS THE EFFECTIVENESS OF DEPRESSION
TREATMENTS IN PATIENTS DIAGNOSED WITH
MAJOR DEPRESSIVE DISORDER, IN BOTH PRIMARY
AND SPECIALTY CARE SETTINGS. IT IS THE LARGEST
AND LONGEST STUDY EVER CONDUCTED TO
EVALUATE DEPRESSION TREATMENT.
• OVER A SEVEN-YEAR PERIOD, THE STUDY
ENROLLED 4,041 OUTPATIENTS, AGES 18-75 YEARS,
FROM 41 CLINICAL SITES AROUND THE COUNTRY,

27. CONTD…
• OF THE INITIAL 4,041 PARTICIPANTS, 1,165 WERE
EXCLUDED BECAUSE THEY EITHER DID NOT MEET
THE STUDY REQUIREMENTS OF HAVING “AT LEAST
MODERATE” DEPRESSION (BASED ON A RATING
SCALE USED IN THE STUDY) OR THEY CHOSE NOT
TO PARTICIPATE.
• THUS, 2,876 “EVALUABLE” PEOPLE WERE INCLUDED
IN LEVEL 1 RESULTS.
• LEVEL 2 RESULTS INCLUDE 1,439 PEOPLE WHO DID
NOT BECOME SYMPTOM-FREE IN LEVEL 1 AND
CHOSE TO CONTINUE.
• LEVEL 3 RESULTS INCLUDE 377 PEOPLE
• LEVEL 4 RESULTS INCLUDE 142 PEOPLE

28. CONTD…
• IN MOST CLINICAL TRIALS OF TREATMENT FOR
DEPRESSION, THE MEASURE OF SUCCESS
(OUTCOME) IS CALLED “RESPONSE” TO TREATMENT,
WHICH MEANS THAT THE PERSON’S SYMPTOMS
HAVE DECREASED TO AT LEAST HALF OF WHAT
THEY WERE AT THE START OF THE TRIAL.
• IN STAR*D, THE OUTCOME MEASURE WAS A
“REMISSION” OF DEPRESSIVE SYMPTOMS—
BECOMING SYMPTOM-FREE.

29. STAR*D CHART

30. SUMMARY OF STAR*D STUDY
• RESULTS FROM LEVEL 2 INDICATE THAT IF A FIRST TREATMENT
WITH ONE SSRI FAILS, ABOUT ONE IN FOUR PEOPLE WHO
CHOOSE TO SWITCH TO ANOTHER MEDICATION WILL GET
BETTER, REGARDLESS OF WHETHER THE SECOND MEDICATION IS
ANOTHER SSRI OR A MEDICATION OF A DIFFERENT CLASS.
• IF PATIENTS CHOOSE TO ADD A NEW MEDICATION TO THE
EXISTING SSRI, ABOUT ONE IN THREE PEOPLE WILL GET BETTER.
• IT APPEARS TO MAKE SOME, BUT NOT MUCH, DIFFERENCE IF
THE SECOND MEDICATION IS AN ANTIDEPRESSANT FROM A
DIFFERENT CLASS (E.G. BUPROPION) OR IF IT IS A MEDICATION
THAT IS MEANT TO ENHANCE THE SSRI (E.G. BUSPIRONE).
• THE SWITCH GROUP AND THE ADD-ON GROUP CANNOT BE
DIRECTLY COMPARED TO EACH OTHER, IT IS NOT KNOWN
WHETHER PATIENTS ARE MORE LIKELY TO GET BETTER BY
SWITCHING MEDICATIONS OR BY ADDING ANOTHER
MEDICATION.

31. CONTD…
• RESULTS FROM LEVEL 3 APPLY TO THOSE WHO DO NOT GET BETTER
AFTER TWO MEDICATION TREATMENT STEPS.
• BY SWITCHING TO A DIFFERENT ANTIDEPRESSANT MEDICATION,
ABOUT ONE IN SEVEN PEOPLE WILL GET BETTER.
• BY ADDING A NEW MEDICATION TO THE EXISTING ONE, ABOUT
ONE IN FIVE PEOPLE WILL GET BETTER.
• LEVEL 3 RESULTS ALSO TELL US THAT ADDING T3 MAY HAVE SOME
ADVANTAGES OVER ADDING LITHIUM FOR PATIENTS WHO HAVE
TRIED TWO OTHER TREATMENTS WITHOUT SUCCESS.
• FINALLY, FOR PATIENTS WITH THE MOST TREATMENT-RESISTANT
DEPRESSION, LEVEL 4 RESULTS SUGGEST THAT TRANYLCYPROMINE
IS LIMITED IN ITS TOLERABILITY AND THAT UP TO 10 PERCENT MAY
BENEFIT FROM THE COMBINATION OF VENLAFAXINE-
XR/MIRTAZAPINE

32. FIRST CHOICE TREATMENTS FOR
TREATMENT RESISTANT DEPRESSION
• TO ADD LITHIUM( SERUM LEVEL 0.4- 1.0MMOL/L)
• ECT
• TO ADD T3(20- 50MCG)
• TO COMBINE OLANZAPINE AND FLUOXETINE (12.5MG+ 50MG OD)
• TO ADD QUETIAPINE(150MG OR 300MG A DAY)TO SSRI/SNRI
• TO RISPERIDONE (0.5-3MG/DAY) TO ANTIDEPRESSANT
• TO ADD ARIPIPRAZOLE (5-20MG/DAY) TO ANTIDEPRESSANT
• SSRI+ BUPROPRION (UPTO 400MG/DAY)
• SSRIOR VENLAFAXINE+ MIANSERIN (30MG/DAY) OR
MIRTAZAPINE(30-45MG/DAY)

33. SECOND CHOICE
• TO ADD LAMOTRIGINE( 200MG AND
400MG A DAY)
• TO ADD PINDOLOL (5 MG TDS OR 7.5 MG
OD)
• SSRI+ BUSPIRONE ( UPTO 60 MG/ DAY)
• VENLAFAXINE ( >200MG/ DAY)

34. THIRD CHOICE
• TO ADD AMANTADINE ( UPTO 300MG/ DAY)(Stryjer R
et al.)
• TO ADD CARBERGOLINE 2MG/DAY (Takahashi H et al)
• TO ADD CLONAZEPAM 0.5-1.0MG/DAY (Smith WT et
al.)
• TO ADD MECAMYLAMINE (UPTO 10MG/DAY)(George
TP et al.)
• TO ADD METYRAPONE 1000MG/ DAY ( Jahn H et al.)
• TO ADD TRYPTOPHAN 2-3 G TDS ( Angst J et al.)
• TO ADD YOHIMBINE ( UPTO 30MG/DAY)(Sanacora G
et al.)
• TO ADD ZINC ( 25 MG ZN+/ DAY)( Siwek M et al.)
• TO ADD ZIPRASIDONE (UPTO 160MG/DAY) (
Papakostas GI et al.)
• TO COMBINE MAOI AND TCA, EG. TRIMIPRAMINE
AND PHENELZINE ( White K et al, Kennedy N et al.,
Connolly KR et al.)

35. CONTD…
• DEXAMETHASONE 3-4MG /DAY ( Dinan TG et al.)
• KETOCONAZOLE 400-800MG/DAY( WolkowitzOM et
al.)
• MODAFINIL 100- 400MG /DAY (DeBattista C et al)
• NEMIFITIDE (40- 240MG/DAY SC) (Feighner JP et al)
• NORTRIPTYLINE+ LITHIUM (Nierenberg AA et al)
• OESTROGENS ( various regimens)
• OMEGA-3-TRIGLYCERIDES (Peet M et al)
• PRAMIPREXOLE 0.125- 5MG/DAY (Whiskey E et al.)
• RILUZOLE 100-200MG/DAY ( Zarate CA Jr et al)
• S-ADENOSYL- L- METHIONINE 400MG/DAY IM;
1600 MG /DAY ORAL (Pancheri P et al.)
• SSRI + TCA ( Taylor D.)

36. • rTMS (Huang CC et al)
• TCA ( Malhi GS et al)
• TESTOSTERONE GEL ( Pope HG Jr et al)
• VAGUS NERVE STIMULATION ( Matthews
K et al)
• VENLAFAXINE- VERY HIGH DOSE (UPTO
600 MG /DAY)(Harrison CL et al)
• VENLAFAXINE + IV CLOMIPRAMINE
(Fountoulakis KN et al)

37. THYROID HORMONES
• THYROID HORMONES HAVE MANY COMPLEX CELLULAR
ACTIONS, INCLUDING ACTIONS THAT MAY BOOST
MONOAMINE NEUROTRANSMITTERS .
• T3 TREATMENT OF THE DEPRESSED PATIENT RESISTANT TO
TCA WAS FIRST REPORTED BENEFICIAL IN AN OPEN STUDY
WITHOUT A PLACEBO GROUP(AMERICAN JOURNAL OF
PSYCHIATRY 1970)
• THE POSITIVE EFFECT OF 25–50 MG T3 DAILY AS AN
ADJUNCTIVE THERAPY HAS BEEN CONFIRMED IN MANY
STUDIES, INCLUDING A RECENT METAANALYSIS ( ARCHIVES
OF GENERAL PSYCHIATRY 1996 53 842–848.), WHICH
INCLUDED FOUR RANDOMIZED DOUBLEBLIND TRIALS (IN
TOTAL 69 PATIENTS) AND THREE UNBLINDED STUDIES USING
HISTORICAL CONTROLS (IN TOTAL 185 PATIENTS).
• THIS ANALYSIS ALSO DISCUSSED IN DETAIL THOSE STUDIES
WHICH DID NOT FIND ANY BENEFICIAL EFFECT OF T3.
OVERALL THE ADDITION OF T3 TO TCA INCREASED THE
RESPONSE RATE SIGNIFICANTLY FROM 24 TO 57%.

38. CONTD…
• IN ANOTHER RANDOMIZED DOUBLE-BLIND STUDY,
JOFFE ET AL. COMPARED THE ABILITY OF T3 AND
LITHIUM TO CONVERT NONRESPONDERS TO TCA
INTO RESPONDERS, I.E. REDUCE THE DEPRESSIVE
SYMPTOMS ON A HAMILTON RATING SCALE.
• T3 WAS EQUALLY EFFECTIVE AS LITHIUM, AND BOTH
DRUGS WERE SUPERIOR TO PLACEBO.( ARCHIVES OF
GENERAL PSYCHIATRY 1993.)

39. S-ADENOSYL METHIONINE
• LMETHYL FOLATE ASSIST IN THE FORMATION OF
TETRAHYDROBIOPTERIN( BIOPTERIN), CRITICAL COFACTOR FOR
SYNTHESIS OF MONOAMINES INCLUDING DOPAMINE
• L METHYL FOLATE CAN INCREASE METHYLATION OF THE
PROMOTER FOR THE GENE OF THE ENZYME COMT( CATECHOL-O-
METHYL TRANSFERASE), WHICH INACTIVATES DOPAMINE.

40. ELECTROCONVULSIVE
THERAPY
• HIGHLY EFFECTIVE, THOUGHT TO BE RELATED TO THE
PROBABLE MOBILISATION OF NEUROTRANSMITTERS
CAUSED BY THE SEIZURE.
• ONSET OF ACTION EVEN AFTER A SINGLE DOSE
• HIGH RELAPSE RATE IN PATIENTS TREATED WITH ONLY
ECT.
• MAINTENANCE ECT + ANTIDEPRESSANTS- EFFECTIVE.

41. PSYCHOTHERAPY
• A VARIETY OF PSYCHOTHERAPEUTIC TECHNIQUES CAN
BE USED TO TREAT DEPRESSION
– CBT
– INTERPERSONAL PSYCHOTHERAPY,
– NONDIRECTIVE COUNSELING,
– BEFRIENDING,
– PROBLEM-SOLVING THERAPY,
– PSYCHODYNAMIC PSYCHOTHERAPY,
– GROUP PSYCHOEDUCATION,
– COGNITIVE BEHAVIOR ANALYSIS, AND EXERCISE.
( AMERICAN PSYCHIATRIC ASSOCIATION. PRACTICE
GUIDELINE FOR THE TREATMENT OF PATIENTS WITH MAJOR
DEPRESSIVE DISORDER. 2ND ED.WASHINGTON, DC:
AMERICAN PSYCHIATRIC ASSOCIATION; 2000.)

42. CONTD
• THE STAR*D TRIAL FOUND THAT PATIENTS WHO
RECEIVED CBT AFTER FAILING TO RESPOND TO
CITALOPRAM (WITH OR WITHOUT CONTINUED
CITALOPRAM) HAD SIMILAR RATES OF RESPONSE (I.E.,
AT LEAST 50 PERCENT IMPROVEMENT IN SYMPTOMS
COMPARED WITH BASELINE) AND REMISSION (I.E.,
RESOLUTION OF SYMPTOMS) AS THOSE WHO RECEIVED
OTHER MEDICATION REGIMENS.
• PATIENTS WHO RECEIVED CBT ALONE (RATHER THAN
IN CONJUNCTION WITH CITALOPRAM) ACHIEVED
REMISSION LESS RAPIDLY, BUT THEY ALSO HAD FEWER
ADVERSE EFFECTS THAN THOSE WHO WERE SWITCHED
TO OTHER MEDICATIONS.

43. OTHERS
• OTHERS ARE TRANSCRANIAL MAGNETIC STIMULATION,
MAGNETIC SEIZURE THERAPY, DEEP BRAIN STIMULATION.
• APPROVAL OF AN RTMS DEVICE WAS GRANTED BY THE FDA
IN OCTOBER 2008.
• CONVENTIONAL RTMS PROTOCOLS TYPICALLY TARGET THE
LEFT DLPFC. THE DISCHARGE FREQUENCY OF STIMULATION
(IE, THE NUMBER OF TIMES THE MAGNETIC FIELD IS
GENERATED AND THE CURRENT INDUCED ON BRAIN
TISSUE) IS USUALLY AT A FREQUENCY OF 10 HZ; THIS HIGH-
FREQUENCY STIMULATION INCREASES CORTICAL
EXCITABILITY.
• RTMS IS A NON-INVASIVE PROCEDURE IN WHICH
CEREBRAL ELECTRICAL ACTIVITY IS INFLUENCED BY A
RAPIDLY CHANGING MAGNETIC FIELD.
• THE MAGNETIC FIELD IS CREATED BY A PLASTIC-ENCASED
COIL WHICH IS PLACED OVER THE PATIENT’S SCALP.

44. CONTD…
• THE MAGNETIC FIELD CAN BE DIRECTED ONTO SPECIFIC AREAS OF
THE BRAIN.
• RTMS CAN MODULATE CEREBRAL ACTIVITY BY LOW OR HIGH
FREQUENCIES.
• IN CONTRAST TO ECT, RTMS CAN INDUCE CORTICAL ELECTRICAL
ACTIVITY WITHOUT CAUSING A SEIZURE; IT IS SUB-CONVULSIVE
AND THEREFORE DOES NOT REQUIRE ANAESTHESIA.
• PREVIOUS RESEARCH HAS SHOWN THAT TMS IS A SAFE AND
EFFECTIVE ACUTE TREATMENT OPTION FOR PATIENTS WITH TR-
MDD.
• HOWEVER, THE LONG-TERM EFFICACY AND DURABILITY OF THE
TREATMENT IN THIS PATIENT POPULATION WERE UNCLEAR.
• TRANSCRANIAL MAGNETIC STIMULATION (TMS) APPEARS TO
OFFER LONG-TERM EFFICACY IN PATIENTS WITH TREATMENT-
RESISTANT MAJOR DEPRESSIVE DISORDER (TR-MDD), NEW
RESEARCH SHOWS.

45. MAGNETIC SEIZURE THERAPY
• MAGNETIC SEIZURE THERAPY (MST) IS A NOVEL
TREATMENT MODALITY, BY WHICH THERAPEUTIC
SEIZURES ARE INDUCED USING RAPIDLY ALTERNATING
STRONG MAGNETIC FIELDS.
• THE FIRST USE OF THERAPEUTIC MAGNETIC SEIZURE
INDUCTION IN A PSYCHIATRIC PATIENT TOOK PLACE IN
BERN, SWITZERLAND, IN MAY 2000.
• THE MOST FREQUENT ARE MILD HEADACHE, NAUSEA,
AND IRRITATION AT POINT OF STIMULATION.
• THE MOST SERIOUS ADVERSE EFFECT IS THE
INDUCTION OF A SEVERE SEIZURE, WHICH IS
EXCEEDINGLY RARE, WITH AN ESTIMATED INCIDENCE
OF LESS THAN 1 IN 1000 PATIENTS.

46. VAGAL NERVE STIMULATION
• VAGAL NERVE STIMULATION REFERS TO ELECTRICAL
STIMULATION OF THE CERVICAL PORTION OF THE LEFT VAGUS
NERVE.
• THIS TREATMENT WAS APPROVED IN 2005 FOR TREATMENT-
RESISTANT DEPRESSION (INADEQUATE RESPONSE TO AT LEAST
FOUR ANTIDEPRESSANT DRUGS).
• THE ONLY RCT OF THIS THERAPY INCLUDED 235 PATIENTS AND
FOUND NO DIFFERENCE IN THE PRIMARY OUTCOME BETWEEN
ACTIVE THERAPY AND SHAM GROUPS (RUSH AJ, MARANGELL
LB, SACKEIM HA, ET AL.)
• IN ADDITION, TWO SERIOUS ADVERSE EVENTS OCCURRED IN
THE ACTIVE THERAPY GROUP: ONE INFECTION THAT REQUIRED
REMOVAL OF THE DEVICE, AND ONE SUICIDE.
• SIDE EFFECTS OF VAGAL NERVE STIMULATION INCLUDE
HOARSENESS, HEADACHE, NECK PAIN, AND COUGH.

47. DEEP BRAIN STIMULATION
MAYBERG AND COLLEAGUES DEMONSTRATED
THAT OPEN LABEL SUBCALLOSAL CINGULATE DBS
WAS ASSOCIATED WITH ANTIDEPRESSANT
EFFECTS.

48. NOVEL AGENTS
• TRIPLE REUPTAKE INHIBITORS (TRIS) OR
SEROTONIN-NOREPINEPHRINE- DOPAMINE
REUPTAKE INHIBITORS
• (SNDRIS) ARE IN CLINICAL TESTING.
• SEVERAL DIFFERENT TRIPLE REUPTAKE
INHIBITORS ( EG, AMITIFIDINE, GSK-372475,
BMS-820836, TASOFENSINE,, PRC200-SS, SEP-
225289, AND OTHERS) ARE IN CLINICAL
DEVELOPMENT, SOME WITH ADDITIONAL
PHARMACOLOGIC PROPERTIES (SUCH AS
LUAA24530 WITH 5HT2C, 5HT3,5HT2A AND
ALPHA1A ANTAGONIST PROPERTIES)

49. MULTIMODAL AGENTS
• VILAZODONE- COMBINATION OF SERT
PLUS 5HT1A PARTIAL AGONIST ACTIONS
• VORTIOXETINE: REUPTAKE BLOCKING
MODE(SERT), G PROTEIN RECEPTOR
MODE (5HT1A AND 5HT1B/D PARTIAL
AGONIST,5HT7 ANTAGONIST) AND ION
CHANNEL MODE ( 5HT3 ANTAGONIST)

50. CONTD…
NMDA BLOCKADE: SUBANAESTHETIC DOSES OF
KETAMINE CAN EXERT AN IMMEDIATE ANTIDEPRESSANT
EFFECT IN PATIENTS WITH TREATMENT RESISTANT
UNIPOLAR OR BIPOLAR DEPRESSION, AND CAN
IMMEDIATELY REDUCE SUICIDAL THOUGHTS.

51. CONCLUSION
• TREATMENT RESISTANT DEPRESSION REMAINS A
COMMON CONDITION WITH 50- 60% OF PATIENTS NOT
ACHIEVING MEANINGFUL RESPONSE FOLLOWING
ANTIDEPRESSANT TREATMENT.
• EARLY IDENTIFICATION AND USE OF EFFECTIVE LONG
TERM MAINTAINANCE STRATEGIES ARE IMPORTANT
• NO DEFINITE ALGORITHM EXISTS FOR TREATING
RESISTANT DEPRESSION
• RESEARCH IN THIS AREA HAS ADVANCED CONSIDERABLY
IN RECENT YEARS