TREATMENT RESISTANT DEPRESSION

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.

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

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)

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

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)

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)

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.

• 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.

FUNCTIONAL AND STRUCTURAL CHANGES IN THE LIMBIC AND PFC

AREAS IMPLICATED IN DEPRESSION

SUBSTRATE VOLUME

HISTOLOGICAL CHANGES

METABOLIC ACTIVITY

ANTIDEPRESSANT EFFECTS

ORBITAL/VMPFC ↓ ↓ ↑

ANTERIOR CINGULATE CORTEX

↓↓ METABOLIC ACTIVITY

HIPPOCAMPUS ↓ ↓ ↑ VOLUME

AMYGDALA ↓

↓ METABOLIC ACTIVITY

DLPFC ↓ ↓ ↓

NEUROCHEMICALS IN DEPRESSION

Substrate Concentration/activityCortisol, CRH ↑Proinflammatory cytokines ↑BDNF ↓5-HT neurotransmission ↓NA neurotransmission ↓

PHASES OF TREATMENT

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

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

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

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)

CONTD…

• PATIENTS’ FACTORS– COMPLIANCE– UNUSUAL PHARMACOKINETICS

• PHYSICIAN FACTORS– UNDERDOSING – INADEQUATE LENGTH OF

TREATMENT

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.

FACTORS ASSOCIATED WITH TREATMENT RESISTANCE

• PSYCHIATRIC CO- MORBIDITY• MEDICAL CO- MORBID ILLNESS• GENDER• FAMILY HISTORY• AGE OF ONSET• ILLNESS SEVERITY• CHRONICITY

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

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.

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)

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.

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.

THASE-RUSH TREATMENT-RESISTANT DEPRESSION (TRD) STAGING METHOD

TRD STAGE

CRITERIA

STAGE 1 FAILURE OF AN ADEQUATE TRIAL OF 1 CLASS OF MAJORANTIDEPRESSANT

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 AMONOAMINE OXIDASE INHIBITOR

STAGE 5 STAGE 4 PLUS FAILURE OF AN ADEQUATE COURSE OFELECTROCONVULSIVE THERAPY

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,

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

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.

STAR*D CHART

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.

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

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)

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)

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.)

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.)

• 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)

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%.

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.)

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.

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.

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.)

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.

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.

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.

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.

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.

DEEP BRAIN STIMULATION

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

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)

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)

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.

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