Metabolic side effects of drugs in Psychiatry

METABOLIC SIDE EFFECTS OF DRUGS IN PSYCHIATRY

PRESENTER – DR. SRIRAM.R, PG MD PSYCHIATRY

CHAIRPERSON – DR. ARUL, ASSISTANT PROF OF PSYCHIATRY

ORGANISATION

• WHAT IS METABOLIC SYNDROME (METS)?

• ANTIPSYCHOTIC DRUGS

• CLASSIFICATION

• HISTORICAL PERSPECTIVE – METABOLIC AND CARDIOVASCULAR SIDE EFFECTS

• ANTIPSYCHOTICS AND DIABETES

• METABOLIC SYNDROME

• CARDIOVASCULAR SIDE EFFECTS

• HYPERPROLACTINEMIA

• TO SUMMARIZE

• PATHOPHYSIOLOGY

• FACTORS AFFECTING SIDE EFFECTS

• MANAGEMENT OF WEIGHT GAIN AND METABOLIC ABNORMALITIES

• MONITORING

• NEGLECT IN RECORDING BASIC PARAMETERS IN PATIENTS ON ANTIPSYCHOTICS

ORGANISATION

• ANTIDEPRESSANT DRUGS

• CLASSIFICATION

• SSRI AND WEIGHT GAIN

• PATHOPHYSIOLOGY OF WEIGHT GAIN

• MANAGING WEIGHT GAIN

• REFERENCES

WHAT IS METABOLIC SYNDROME (METS)?

• CLUSTER OF PHYSIOLOGICAL ABNORMALITIES CHARACTERIZED BY INSULIN RESISTANCE LEADING TO INCREASED RISK OF DM TYPE II AND CARDIOVASCULAR RISK

• METS CRITERIA COMPRISE RAISED BLOOD PRESSURE, RAISED TRIGLYCERIDES, LOWERED HIGH-DENSITY LIPOPROTEIN CHOLESTEROL, RAISED FASTING BLOOD GLUCOSE, AND CENTRAL OBESITY ACCORDING TO WC.

• THERE ARE TWO CRITERIA COMMONLY USED – THE WHO CLINICAL CRITERIA FOR METABOLIC SYNDROME AND THE ATP III CLINICAL IDENTIFICATION OF METABOLIC SYNDROME

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METABOLIC SYNDROME

ATP III ATP III A IDF

3 out of 5 3 out of 5 Waist plus any 2 criteria

Waist(cm) Male >102, Female>88

Male >102, Female>88

Male ≥94, Female≥80

BP ≥130/85 ≥130/85 ≥130/85

HDL(mg/dl) Male <40Female <50

Male <40Female <50

Male <40Female <50

Triglycerides(mg/dl)

≥150 ≥150 ≥150

Glucose(mg/dl) ≥110 ≥100 ≥100

Hert et al, 2009

ANTIPSYCHOTIC DRUGS

CLASSIFICATION OF ANTIPSYCHOTIC DRUGS

• PHARMACOLOGICAL CLASSIFICATION

• – FIRST-GENERATION ANTIPSYCHOTICS(LOW POTENCY)

• CHLORPROMAZINE • PROCHLORPERAZINE • THIORIDAZINE

• – FIRST-GENERATION ANTIPSYCHOTICS (HIGH POTENCY) • FLUPHENAZINE • HALOPERIDOL • PIMOZIDE • THIOTHIXENE

• – SECOND GENERATION ANTIPSYCHOTICS • ARIPIPRAZOLE • ASENAPINE • CLOZAPINE • ILOPERIDONE • LURASIDONE • OLANZAPINE • QUETIAPINE • PALIPERIDONE • RISPERIDONE • ZIPRASIDONE

• CHEMICAL CLASSIFICATION

– PHENOTHIAZINES

• ALIPHATIC SIDE CHAIN: CHLORPROMAZINE, TRIFLUPROMAZINE

• PIPERIDINE SIDE CHAIN: THIORIDAZINE

• PIPERAZINE SIDE CHAIN: TRIFLUOPERAZINE, FLUPHENAZINE

– BUTYROPHENONES: HALOPERIDOL, TRIFLUPERIDOL, PENFLURIDOL

– THIOXANTHENES: FLUPENTHIXOL

– OTHER HETEROCYCLICS: PIMOZIDE, LOXAPINE

– ATYPICAL ANTIPSYCHOTICS: CLOZAPINE, RISPERIDONE, OLANZAPINE, QUETIAPINE, ARIPIPRAZOLE, ZIPRASIDONE

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FIRST GENERATION SECOND GENERATION

Chlorpromazine Clozapine Lurasidone

Thioridazine Olanzapine Aripiprazole

Perphenazine Risperidone Blonanserin

Trifluoperazine Quetiapine

Fluphenazine Ziprasidone

Pimozide Amisulpride

Haloperidol Asenapine

Droperidol Iloperidone

Flupenthixol Paliperidone

Zuclopenthixol Zotepine

Clopenthixol Sertindole

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Neurotherapeutics (2009) 6, 78-85

FGA

High affinity and antagonistic effect on dopamine receptors

(D2) (extra pyramidal symptoms)

SGA

Antagonistic effects on both serotonin

and dopamine receptorsHistamine, muscarinic, adrenergic

14

1952

• Use of chlorpromazine in schizophrenia

• Revolutionized the management in psychiatry

1958

• Haloperidol developed• Many similar kind of drugs developed

world wide

1972

• Clozapine trials performed but withdrawn in 1975 due to hematological side effects

• 1989: FDA approved with blood count monitoring

1990s

• Olanzapine, Zotepine, Sertindole, Risperidone and Quetiapine came in market

2000s

• Ziprasidone, Aripiprazole, Asenapine, Iloperidone,

• Blonanserin (2008) and Lurasidone approved by US FDA (2010)

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HISTORICAL PERSPECTIVE-METABOLIC AND CARDIOVASCULAR SIDE EFFECTS• THE METABOLIC AND CARDIO VASCULAR SIDE EFFECTS OF

CONVENTIONAL ANTIPSYCHOTICS HAD BEEN RECOGNIZED JUST AFTER FEW YEARS OF INTRODUCTION

• STUDIES SHOW PHENOTHIAZINE DERIVATIVES TO BE ASSOCIATED WITH CARDIO VASCULAR AND METABOLIC SIDE EFFECTS

• IMPAIRED GLUCOSE TOLERANCE AND DIABETES

KILPATRICK AND WHITE, 1965

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HISTORICAL PERSPECTIVE-METABOLIC SIDE EFFECTS

• THE GLUCOSE TOLERANCE STUDIED IN GROUPS OF PATIENTS DURING LONG-TERM TREATMENT (MORE THAN THREE MONTHS) SHOWED ABERRATIONS IN GLUCOSE TOLERANCE TEST

• 40% PATIENTS CHLORPROMAZINE

• 35% PATIENTS PERPHENAZINE

• 15% PATIENTS CLOPENTHIXOL

AMDISEN A, 1964

• A PROSPECTIVE STUDY OF SCHIZOPHRENIC PATIENTS ON INJECTABLE DEPOT NEUROLEPTIC DRUGS AS MAINTENANCE THERAPY SHOWED A CLINICALLY SIGNIFICANT WEIGHT GAIN IN 55% OF PATIENTS

JOHNSON, 1979

17


• IT IS COMMON FOR THE PATIENTS RECEIVING PHENOTHIAZINE TO GAIN 10-15 POUNDS OF WEIGHT IN THE COURSE OF 1-2 YEAR OF TREATMENT. MANY PATIENTS DISCONTINUE THE MEDICATION DUE TO THIS SIDE EFFECT

JERROLD, 1987

• IN A META-ANALYSIS , OVER A PERIOD OF 10 WEEKS TREATMENT

• CONVENTIONAL AGENTS, MEAN WEIGHT CHANGE RANGED FROM A REDUCTION OF 0.39 KG WITH MOLINDONE TO AN INCREASE OF 3.19 KG WITH THIORIDAZINE

• NEWER ANTIPSYCHOTIC AGENTS, MEAN INCREASES WERE AS FOLLOWS: CLOZAPINE-4.45 KG OLANZAPINE- 4.15 KG; SERTINDOLE- 2.92 KG; RISPERIDONE-2.10 KG; AND ZIPRASIDONE- 0.04 KG.

ALLISON ET AL, 1999

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• IN 2003 FDA REQUIRED ALL MANUFACTURERS OF ATYPICAL ANTIPSYCHOTICS TO INCLUDE A WARNING ABOUT THE RISK OF HYPERGLYCEMIA AND DIABETES

• THE END OF THE CONVENTIONAL ANTIPSYCHOTIC ERA AND THE BEGINNING OF THE ATYPICAL ANTIPSYCHOTIC ERA OF 1990S COINCIDED WITH THE ONSET OF AN EPIDEMIC OF TYPE II DIABETES

STAHL ET AL, 2009

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ANTIPSYCHOTICS AND DIABETES • PERCENTAGE OF PATIENTS WITH SCHIZOPHRENIA RECEIVING ATYPICAL

AND TYPICAL NEUROLEPTIC MEDICATION WITH DIABETES MELLITUS

Sernyak et al,2002

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ANTIPSYCHOTICS AND DIABETES

• META ANALYSIS CONSISTING 11 RCTS

• SGA VS. FGA

SGA RR(95% CI) Number of studies

Risperidone 1.16(0.99-1.35) 6

Quetiapine 1.28(1.14-1.45) 3

Olanzapine 1.28(1.12-1.45) 8

Clozapine 1.39(1.24-1.55) 7

The relative risk of diabetes in patients with schizophrenia prescribed one of the second-generation vs. first-generation antipsychotics was 1.32 (95% CI 1.15–1.51)

Smith et al, 2008

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METABOLIC SYNDROMEStudy N Ethnicity Criteria Prevalenc

e (%) patients

prevalence (%) - population

Brunero et al., 2009

73 schizophrenic patients on Clozapine

Australia IDF 69 21

Huang et al., 2009

650 schizophrenia or schizoaffective in hospital care

Taiwan ATP III 34.9 15

Mattoo et al, 2010

90 psychiatric patient in- patient care

Indian IDF 37.8 25

Sugawara et al, 2010

1186 schizophrenia or schizoaffective in hospital

Japan ATP III 27.5 14.1

Yazici et al, 2011

319 Schizophrenia patients on medication

Turkey ATP III/IDF

34.2/41.7 10.2

Pallava et al, 2012

50 schizophrenic patients on medication

Indian IDF 50 25-36

Chadda et al, 2013

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METABOLIC SYNDROME• STUDY EXPLORING METABOLIC SYNDROME STATUS IN PATIENTS

OF CATIE (CLINICAL ANTIPSYCHOTIC TRIAL OF INTERVENTION EFFECTIVENESS)

• N=660

• COMPARED BETWEEN BASE LINE AND 3 MONTHS OF TREATMENT

• OLANZAPINE AND QUETIAPINE: LARGEST MEAN INCREASE OF WAIST CIRCUMFERENCE (0.7 INCH) FOLLOWED BY RISPERIDONE (0.4 INCH) WITH NO CHANGE IN ZIPRASIDONE GROUP

• OLANZAPINE GROUP HAD INCREASED FASTING TRIGLYCERIDE (+21.5MG/DL) COMPARED TO ZIPRASIDONE (-32.1 MG/DL)

• NO SIGNIFICANT FINDING IN BLOOD PRESSUREMEYER ET AL, 2008

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METABOLIC SYNDROME

META ANALYSIS COMPARING DIFFERENT SGAS

• WEIGHT GAIN :

• RAPID GAIN SLIGHT DECREASE PLATEAU

Weight gain SGA

Maximum elevation Olanzapine , Clozapine

Intermediate elevation Quetiapine, Risperidone, and Sertindole

Low elevation Aripiprazole and Amisulpride

Least elevation Ziprasidone

Kluge, 2010

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METABOLIC SYNDROME

• OLANZAPINE CAUSED THE MOST ELEVATION IN CHOLESTEROL, CLEARLY MORE THAN ARIPIPRAZOLE, RISPERIDONE, AND ZIPRASIDONE

• NO DIFFERENCES WERE FOUND IN COMPARISON BETWEEN AMISULPRIDE, CLOZAPINE AND QUETIAPINE

• QUETIAPINE SHOWED MORE CHOLESTEROL INCREASE THAN RISPERIDONE AND WAS CLOSE TO THAT OBSERVED WITH OLANZAPINE

• SIMILARLY OLANZAPINE AND CLOZAPINE HAD MAXIMUM CHANGE IN THE GLUCOSE UTILIZATION

KLUGE, 2010

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METABOLIC SYNDROME• COMPARISON OF ATYPICALS FOR FIRST EPISODE (CAFE) STUDY

• N=400,

• 16 TO 40 YEARS EITHER SCHIZOPHRENIA, SCHIZOPHRENIFORM OR SCHIZOAFFECTIVE DISORDER

• DURATION 1 MONTH TO 5 YEARS

• BMI ≥ 1 UNIT IN OLANZAPINE GROUP AS COMPARED TO OTHER

PATEL ET AL, 2009

Dosage (mg /day)

12 weeks (≥7kg)

52 weeks(≥7kg)

Metabolic syndrome (n=52 at 52 weeks)

Olanzapine

2.5-20 59.8% 80% 22 (42.3%)

Quetiapine

100-800 29.2% 50% 18(34.6%)

Risperidone

0.5-4 32.5% 57.6% 11(21.15%)

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CARDIOVASCULAR SIDE EFFECTS• STUDY COMPARING 10 YEAR RISK OF CORONARY HEART DISEASE

BETWEEN THE SUBJECTS WHO PARTICIPATED IN CATIE TRIAL AND CONTROLS FROM NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES)-III

• N=689

• AGE, SEX , GENDER MATCHED CONTROLS CATIE NHANES-III

Diabetes 13 % 3 %

Hypertension 27 % 17 %

Lower HDL 43.7 mg/dl 49.3 mg/dl

Total cholesterol levels did not differ between groups

Ten-year CHD risk was significantly elevated in male (9.4% vs. 7.0%) and female (6.3% vs. 4.2%) CATIE patients compared to controls ( p =0.0001)

Goff et al, 2005

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HYPERPROLACTINEMIA

• ROUGHLY EQUATED TO THE POTENCY OF AN ANTIPSYCHOTIC TO BLOCK D2 RECEPTORS

• MORE COMMON WITH FGA THAN SGA EXCEPT RISPERIDONE AND PALIPERIDONE

• SHORT-TERM:

• INCLUDE MENSTRUAL DISTURBANCES

• GALACTORRHEA, SEXUAL DYSFUNCTION, INFERTILITY IN WOMEN

• SEXUAL DYSFUNCTION AND GYNAECOMASTIA IN MEN

• LONG TERM:

• ESTROGEN DEFICIENCY IN WOMEN

• TESTOSTERONE DEFICIENCY IN MEN RESULTING IN DECREASED BONE MINERAL DENSITY

BOSTWICK ET AL, 2009

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Study Sample Type of study Drugs received Significant findings

Smith et al 2002 67 Any one of the FGA for 2 years

Flupenthixol, haloperidol(inj and oral), Pimozide ,chlorpromazine

34% male and 75% female had level more than upper limit

Kim et al 2002 20 female On Risperidone shifted to olanzapine due to prolactin related side effect

Risperidone olanzapine

Decrease in mean prolactin level after shift to olanzapine

Weiden et al 2003

108 FGA104 olanzapineRisperidone 58

Combined analysis of 3 open labeled study

All shifted to Ziprasidone

6 weeks later decreased in 2 groups but no change in olanzapine group

Kane et al 2002 Aripiprazole -204Haloperidol 104Placebo 106

4 weeks randomized double blind placebo controlled

Weaned from previous antipsychotics and started either Aripiprazole or HPL

Mean level decreased in Aripiprazole group from baseline But increased in HPL groupNo change in placebo

First-generation antipsychotics, Risperidone, Paliperidone >Ziprasidone > olanzapine > Quetiapine, clozapine> Aripiprazole

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TO SUMMARIZE• THERE IS DEFINITE RISK OF ANTIPSYCHOTICS FOR

• WEIGHT GAIN

• DIABETES

• CHD

• METABOLIC SYNDROME

• QTC PROLONGATION AND SUDDEN CARDIAC DEATH

• HYPERPROLACTINEMIA

• THE RELATIVE RISK OF METABOLIC ABNORMALITIES IS MORE WITH SECOND GENERATION ANTIPSYCHOTICS AS COMPARED TO FIRST GENERATION

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PATHOPHYSIOLOGY

Increased appetite leading to increased weight and increases BMI

Direct production of atherogenic dyslipidemia

Insulin resistance

Hyperinsulinemia

Beta cell failure

Pre diabetes

Diabetes

Cardio vascular events

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PATHOPHYSIOLOGY• BLOCKADE OF H1 RECEPTORS AND ACTIVATION OF HYPOTHALAMIC AMP

KINASE LEADS TO INCREASED APPETITE. AMP KINASE REVERSES THE ACTIONS OF LEPTIN, THE APPETITE SUPPRESSING HORMONE, AND AMP KINASE MAY BE ACTIVATED BY OREXIN, THE APPETITE INDUCING HORMONE.

• 5HT2C RECEPTOR IS INVOLVED IN THE FEEDING BEHAVIOR

• PERIPHERAL FACTORS UNRELATED TO APPETITE, SUCH AS INCREASED CELLULAR LIPOGENESIS BECAUSE OF ENHANCED ACTIVITY OF FATTY ACID SYNTHASE AND STEAROYL-COA DESATURASE

• HYPOTHETICAL ROLE OF RECEPTOR X: ADIPOSE TISSUE, LIVER AND SKELETAL MUSCLE – AND POSSIBLY THE BRAIN – WHICH WOULD LEAD TO INSULIN RESISTANCE

• HYPOTHETICAL ROLE OF M3 MUSCARINIC CHOLINERGIC RECEPTORS: MORE PROPENSITY FOR DEVELOPING DIABETIC KETOACIDOSIS

STAHL ET AL, 2009

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PATHOPHYSIOLOGY

• GENOME WIDE ASSOCIATION STUDIES (GWAS) TO SEARCH FOR GENETIC VARIATION AFFECTING THE SUSCEPTIBILITY TO METABOLIC SIDE EFFECTS

• SCHIZOPHRENIA PATIENTS FROM CATIE TRIAL

• DIFFERENT SNPS AND INTRAGENIC MARKERS WERE FOUND TO BE SIGNIFICANT IN THE CHANGE OF METABOLIC PARAMETERS

• SNP IN MEIS2 GENE MEDIATED THE EFFECTS OF RISPERIDONE ON WAIST CIRCUMFERENCE

ADKINS ET AL, 2011

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PATHOPHYSIOLOGY

Metabolic

Weight Gain, esp. abdominal obesity

Impaired Glucose Metabolism• Hyperglycemia• Type 2 DM

Dyslipidemia• Hyper cholesterolmia• Hypertriglyceridemia• Low HDL

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FACTORS AFFECTING SIDE EFFECTS

• Family History of obesity

• Parental BMI• Genetic Factors

• Cannabis use• Smoking • BMI• Negative

Symptoms• ethnicity

• Long term treatment

• Polypharmacy• High dosage• Type of

medications

• History of prior treatment

• Episode of illness

FAMILIAL PERSONAL

TREATMENTILLNESS

Hasnain et al, 2008

35

FACTORS AFFECTING SIDE EFFECTS

Diabetes

Dyslipidemia

Metabolic Syndrome

Vascular Inflammati

on and Hyper -

coagulation

Increased Mortality and

Morbidity

36

ANIMAL STUDY

• TO STUDY THE SUSCEPTIBILITY OF ANTIPSYCHOTIC INDUCED METABOLIC CHANGES, 76 MICE WERE TREATED WITH HALOPERIDOL, OLANZAPINE OR CLOZAPINE FOR 7 DAYS

• FUNCTIONAL ANALYSIS WAS CONDUCTED ON THE PUTATIVE TARGETS OF ALTERED MICRORNA

• METABOLIC PATHWAYS WERE ENRICHED IN OLANZAPINE AND CLOZAPINE TREATMENTS, POSSIBLY ASSOCIATED WITH THEIR WEIGHT GAIN SIDE EFFECTS

• SUGGESTS A ROLE FOR MICRORNA IN THE MECHANISM OF ACTION AND THE METABOLIC SIDE EFFECTS OF THE ATYPICAL ANTIPSYCHOTIC DRUGS

SANTARELLI ET AL, 2013

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MANAGEMENT FOR WEIGHT GAIN AND METABOLIC ABNORMALITIES

THE 2010 PORT GUIDELINES:

• EARLY BEHAVIORAL INTERVENTION

• PHARMACOTHERAPY SWITCHING FROM ONE AGENT TO ANOTHER

ADDITION OF ANOTHER MEDICATION BEFORE THE INITIATION OF ANTIPSYCHOTIC TREATMENT

ADDITION OF ANOTHER MEDICATION DURING THE ANTIPSYCHOTIC TREATMENT

BUCHANAN ET AL. 2010

EARLY BEHAVIOURAL INTERVENTION

• 61 TREATMENT NAIVE PSYCHOTIC PATIENTS

• RANDOMLY ASSIGNED TO OLANZAPINE, RISPERIDONE OR HALOPERIDOL

• FURTHER RANDOMIZED TO EITHER EARLY BEHAVIORAL INTERVENTION (EBI) OR ROUTINE CARE INTERVENTION (RCI)

• EBI: 8 FLEXIBLE INTERVENTION MODULES THAT INCORPORATED BEHAVIOURAL INTERVENTIONS, NUTRITION, AND EXERCISE) (10-14 SESSIONS OVER 3 M)

• RCI: PATIENTS WERE INFORMED ABOUT POTENTIAL WEIGHT GAIN AND ADVISED TO INCREASE THEIR EXERCISE AND LIMIT FOOD INTAKE

JIMENEZ ET AL,2006

42

EARLY BEHAVIOURAL INTERVENTION

J Clin Psychiatry. 2006 Aug;67(8):1253-60

Jimenez et al,2006

43

SWITCHING OF ANTIPSYCHOTICS

STUDY SAMPLE SIZE

SHIFT RESULTS PSYCHOPATHOLOGY

Newcomer et al. 2008Multicentric double blind RCT

173 Random assignment of switch from olanzapine to Aripiprazole or stay on olanzapine

Improvement in metabolic parameters and weight In the Aripiprazole group

Not discussed

Stroup et al. 2011

89

98

olanzapine, Quetiapine or risperidoneto Aripiprazole

Remained on the same

Significant weight reductions andan improvement of metabolic parameters in the Aripiprazole Group

Not discussed

• The switch to Ziprasidone might have some advantages compared to staying on Risperidone/olanzapine, but the evidence is limited

• Switch to Aripiprazole is a promising approach for treating antipsychotic induced weight gain

44

SWITCHING OF ANTIPSYCHOTICS

Buckley et al, 2008

45

ADDITION OF ANOTHER MEDICATION

• AMANTADINE:

• CASE REPORTS

• RISK OF FLARING PSYCHOSIS

• H2 RECEPTOR ANTAGONIST

• NIZATIDINE :

DOUBLE-BLIND RCT. PATIENTS ON OLANZAPINE (5 – 20 MG/DAY) SIGNIFICANTLY LESS WEIGHT GAIN AFTER 4 WEEKS ADD-ON TREATMENT WITH DOSES OF 300 MG BD

RESULT NOT SIGNIFICANT AFTER 24 WEEKS CAVAZZONI ET AL. 2003

46

ADDITION OF ANOTHER MEDICATION METFORMIN:

Study Method Participants Intervention Result

Bapista et al,2006

Randomized double blinding, 14 weeks

Schizophrenia and schizoaffective n=40

Olanzapine plus metformin or placebo(Metformin=850 to 1750)

In meta-analysis, weight reduction was 5.02% with metforminThe adverse events reportedwith metformin were similar to placebo groups

Bapista et al, 2007

Do,12 weeks Schizophrenia and Bipolar n=80

Do, Metformin 850 to 2550

Wu et al, 2008 Do, 12 weeks Schizophrenia n=40

Do, Metformin 750

Wu et al, 2008 Do, 14 weeks Schizophrenia n=64

Do, Metformin 750

Praharaj et al, 2011

47

ADDITION OF ANOTHER MEDICATION

TOPIRAMATE:

• N=72 RANDOMIZED TO RECEIVE OLANZAPINE+PLACEBO OR OLANZAPINE+TOPIRAMATE(100MG/DAY)

• RESULTS: IN THE TOPIRAMATE GROUP THERE WAS FOUND TO BE REDUCTION OF MEAN WEIGHT OF 1.27±2.28 KG , DECREASE IN GLUCOSE CHOLESTEROL AND TRIGLYCERIDE LEVEL

NARULA ET AL. 2010

• TOPIRAMATE WITH CLOZAPINE : NO WEIGHT LOSS IN A DOUBLE-BLIND, PLACEBO-CONTROLLED RCT IN WHICH WEIGHT GAIN WAS NOT THE PRIMARY OUTCOME PARAMETER

MUSCATELLO ET AL. 2011

• SOME CASE REPORTS BUT NO CONTROLLED TRIALS

• MODAFINIL

• ORLISTAT

• ROSAGLITAZONE

49

OTHER GUIDELINES

Risk Factors ADA-APA Guidelines(2004) Mount Sinai Guidelines(2004)

Weight gain

If patient gains 5% of initial weight, consider cross-titration of medication.

Closer monitoring, adjunctive treatment for weight loss, or change in medication. If on a medication with greater risk of weight gain, consider switching.

Referral to weight management program.

Diabetes or glucoseintolerance

Consider change to lower risk medication. Refer to diabetes education program and clinician with experience treating diabetes.

Referral to a primary care physician or internist.

DyslipidemiaConsider change to lower risk medication. May consider specialist referral.

Dietary advice to reduce fat intake.Pharmacologic intervention with a lipid-lowering agent.

50

MONITORINGRisk factors ADA-APA

Guidelines(2004)Mount

Sinai Guidelines (2004)

NICE guidelines (2010)

Personal and family history of risk factors

Baseline then annually

Baseline Baseline

Ethnicity Not addressed Baseline Baseline

Smoking status Not addressed Baseline Baseline

Weight, height (BMI) Baseline 4, 8 and 12 weeks then quarterly

Baseline and every 6 months

Every weekly or every clinic visit

Waist circumference Baseline then annually

Baseline and every 6 months

Not addressed

Blood Pressure Baseline 12 weeks then annually

Not addressed Baseline, 12 weeks, annual

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MONITORING

Risk FactorsADA-APA


Sinai Guidelines(2004)

NICE guidelines (2010)/Maudsley 2012

Fasting Plasma Glucose

Baseline, at 12 weeks, then annually

Baseline, If risk factors for diabetes, at 4 months, then annually. If gaining weight, every 4 months.

Baseline, 12 weeks and annually

Lipid profile

Baseline, at 12 weeks, then every 5 years if normal lipid profile

Baseline, every 2 years for normal LDL, every 6 months if LDL > 130mg/dl

Baseline,12 weeks and annually

EKGBaseline and annually

Baseline. Subsequent EKG if symptoms present.


Signs/Symptoms of Diabetes

BaselineBaseline and at regular intervals

Baseline and 12 weeks and annually

52

MONITORINGRisk factors ADA-APA


Sinai Guidelines(2004)

NICE guidelines (2010)/Maudsley 2012

Hemoglobin A1C Not addressed

Recommended alternative when measurement of plasma glucose level is not feasible


Target:

• BP: <140/90

• BMI<25 kg/m2

• Fasting Glucose<6.0 mmol/l, Non fasting <7.8mmol/l

• Glycosylated Hb: If no h/o DM <6%, If H/O 6.5-

7.5(individualized)

• Total Cholesterol <5.0mmol/l or 4 mmol/l If established DM

or CVD • LDL <3 mmol/l or <2.0mmol/l if established DM or CVD 30%

reduction after starting of Statins

53

HYPERPROLACTINEMIA

GUIDELINES :

• USE LOWEST EFFECTIVE DOSAGE

• USE OF PROLACTIN SPARING ANTIPSYCHOTICS

• ADD ANOTHER ANTIPSYCHOTIC THAT NORMALIZES PROLACTIN LIKE ARIPIPRAZOLE

• OBTAIN A BASELINE PROLACTIN LEVEL IF ANY SYMPTOMS OF RAISED PROLACTIN PRESENT

• IF STILL THE SYMPTOMS EXPLAINED BY RAISED PROLACTIN USE OF BROMOCRIPTINE OR CABERGOLINE (RISK OF INCREASING PSYCHOTIC SYMPTOMS )

BOSTWICK ET AL, 2009

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NEGLECT IN RECORDING BASIC PARAMETERS IN PATIENTS ON ANTIPSYCHOTICS

CLINICAL RECORDS OF 1966 ELIGIBLE PATIENTS UNDER THE CARE OF CLINICAL TEAMS IN 21 MENTAL HEALTH SERVICES ACROSS THE UK (2005)

Barnes et al, 2007

It was recommended these parameters to be reviewed once a year, from the guidelines

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NEGLECT IN RECORDING BASIC PARAMETERS IN PATIENTS ON ANTIPSYCHOTICS

• ALTHOUGH BLOOD PRESSURE AND OBESITY ARE RELATIVELY SIMPLE AND EASY TO MEASURE, THE SCREENING RATES OVER THE YEAR FOR THESE VARIABLES WERE NO BETTER THAN THOSE FOR TESTS REQUIRING BLOOD SAMPLES

• INCREASED RATE OF SCREENING WERE SEEN FOR

• PATIENTS ON CLOZAPINE

• ADVANCING AGE

• COMORBID DIAGNOSIS OF DIABETES, DYSLIPIDEMIA OR HYPERTENSION Barnes et al,

2007

ANTIDEPRESSANT DRUGS

• IN 1998, THE FIRST SSRI, FLUOXETINE, WAS PRODUCED IN THE US.

• FLUOXETINE WAS SUPERIOR TO TRICYCLIC ANTIDEPRESSANTS (TCAS) IN TERMS OF REDUCING SIDE EFFECTS AND SELECTIVITY FOR SEROTONIN RECEPTORS, AND IT HAD A SIMILAR LEVEL OF EFFECTIVENESS AS THE TCAS.

• RESULTS OF A RANDOMIZED CLINICAL STUDY SUGGESTED THAT WEIGHT GAIN MIGHT BE A SIDE EFFECT OF LONG-TERM PAROXETINE USE BUT NOT OF THE USE OF SERTRALINE OR FLUOXETINE (MICHELSON ET AL, 1999)

SSRI AND WEIGHT GAIN

• UNCONTROLLED STUDIES HAVE REPORTED MEAN WEIGHT GAINS OF 15 LB (6.75 KG) FOR SERTRALINE, 21 LB (9.45 KG) FOR FLUOXETINE, AND 24 LB (10.80 KG) FOR PAROXETINE AFTER 6 TO 12 MONTHS OF THERAPY

SUSSMAN ET AL, 1998

• ASSOCIATION BETWEEN USE OF SSRIS AS A GROUP (N = 461) AND ABDOMINAL OBESITY (OR = 1.40, 95% CI = 1.08 TO 1.81) AND HYPERCHOLESTEROLEMIA (OR = 1.36, 95% CI = 1.07 TO 1.73) AFTER ADJUSTING FOR MULTIPLE POSSIBLE CONFOUNDERS. THERE WAS ALSO A TREND TOWARD AN ASSOCIATION BETWEEN SSRI USE AND DIABETES. IN A SUBGROUP ANALYSIS OF SUBJECTS TAKING SSRIS, THE USE OF PAROXETINE (N = 187) WAS MARKEDLY ASSOCIATED WITH BOTH GENERAL AND ABDOMINAL OBESITY BUT NOT WITH HYPERCHOLESTEROLEMIA. IN CONTRAST, THE USE OF CITALOPRAM (N = 142) WAS NOT ASSOCIATED WITH ANY OF THE METABOLIC OUTCOME VARIABLES, WHILE THE USE OF ANY OTHER SSRI (SERTRALINE, FLUOXETINE, OR FLUVOXAMINE) (N = 131) AS A MIXED SUBGROUP WAS ASSOCIATED WITH BOTH ABDOMINAL OBESITY AND HYPERCHOLESTEROLEMIA.

READER ET AL, 2006

BEYAZYUZ ET AL, 2013

• TO DESCRIBE THE EFFECTS OF SSRIS ON THE METABOLIC PARAMETERS OF DRUG-NAIVE FIRST EPISODE PATIENTS WITH GENERALIZED ANXIETY DISORDER.

• NINETY-SEVEN FEMALE PATIENTS AGED 20-41 YEARS WITHOUT ANY METABOLIC OR PSYCHIATRIC COMORBIDITY WERE INCLUDED IN THE STUDY. FLUOXETINE, SERTRALINE, PAROXETINE, CITALOPRAM AND ESCITALOPRAM WERE RANDOMLY GIVEN TO THE PATIENTS.

• METABOLIC PARAMETERS, INCLUDING BMI, WAIST CIRCUMFERENCE AND THE LEVELS OF FASTING GLUCOSE, TOTAL CHOLESTEROL, TRIGLYCERIDE, HDL, LDL AND BLOOD PRESSURE, WERE MEASURED BEFORE AND AFTER 16 WEEKS OF TREATMENT.

• IN THE PAROXETINE GROUP, THERE WAS A SIGNIFICANT INCREASE IN THE PARAMETERS OF WEIGHT, BMI, WAIST CIRCUMFERENCE, FASTING GLUCOSE, TOTAL CHOLESTEROL, LDL AND TRIGLYCERIDE AFTER 16 WEEKS OF TREATMENT. THERE WERE SIGNIFICANT INCREASES IN THE LEVELS OF TRIGLYCERIDE IN THE CITALOPRAM AND ESCITALOPRAM GROUPS. IN THE SERTRALINE GROUP, THE TOTAL CHOLESTEROL LEVEL INCREASED AFTER TREATMENT. IN THE FLUOXETINE GROUP, THERE WERE SIGNIFICANT REDUCTIONS IN THE PARAMETERS OF WEIGHT, TOTAL CHOLESTEROL AND TRIGLYCERIDE.

SERRETTI ET AL, 2010

• META ANALYSIS - STUDIES REPORTING BODY WEIGHT CHANGES DURING TREATMENT WITH DIFFERENT ANTIDEPRESSANTS WERE SELECTED FOR ELIGIBILITY. FINALLY, 116 STUDIES WERE INCLUDED IN THE ANALYSIS.

• QUANTITATIVE RESULTS EVIDENCED THAT AMITRIPTYLINE, MIRTAZAPINE, AND PAROXETINE WERE ASSOCIATED WITH A GREATER RISK OF WEIGHT GAIN. IN CONTRAST, SOME WEIGHT LOSS OCCURS WITH FLUOXETINE AND BUPROPION, ALTHOUGH THE EFFECT OF FLUOXETINE APPEARS TO BE LIMITED TO THE ACUTE PHASE OF TREATMENT.

62

PATHOPHYSIOLOGY OF WEIGHT GAIN

• BLOCKADE OF H1 RECEPTORS AND ACTIVATION OF HYPOTHALAMIC AMP KINASE LEADS TO INCREASED APPETITE

• 5HT2C RECEPTOR IS INVOLVED IN THE FEEDING BEHAVIOR

• PERIPHERAL FACTORS UNRELATED TO APPETITE, SUCH AS INCREASED CELLULAR LIPOGENESIS BECAUSE OF ENHANCED ACTIVITY OF FATTY ACID SYNTHASE AND STEAROYL-COA DESATURASE

• HYPOTHETICAL ROLE OF RECEPTOR X: ADIPOSE TISSUE, LIVER AND SKELETAL MUSCLE – AND POSSIBLY THE BRAIN – WHICH WOULD LEAD TO INSULIN RESISTANCE

• HYPOTHETICAL ROLE OF M3 MUSCARINIC CHOLINERGIC RECEPTORS: MORE PROPENSITY FOR DEVELOPING DIABETIC KETOACIDOSIS

STAHL ET AL, 2009

63

PATHOPHYSIOLOGY OF WEIGHT GAIN• PAROXETINE (SSRI), MIRTAZAPINE (NASSA/TETCA), AND AMITRIPTYLINE

(TCA) ALL HAVE SOMETHING IN COMMON. THEY ALL HAVE AFFINITY FOR THE HISTAMINE RECEPTOR AND ARE

ANTICHOLINERGIC.

• ALPHA RECEPTOR BLOCKERS ARE ALSO ASSOCIATED WITH WEIGHT GAIN, AND MIRTAZAPINE AND AMITRIPTYLINE HAVE ALPHA RECEPTOR BLOCKING

ACTION.

• DRUGS THAT CAUSE WEIGHT LOSS HAVE MORE AFFINITY FOR DOPAMINE AND ENHANCE SEROTONIN FUNCTIO

N.

• BUPROPION MAXIMIZES NOREPINEPHRINE AND DOPAMINE, AND HAS ALMOST NO HISTAMINE OR ANTICHOLINERGIC EFFECT AT ALL AND SO IT CAUSES

WEIGHT LOSS.

MANAGING WEIGHT GAIN

• IF WEIGHT GAIN HAS OCCURRED, A SAFE INITIAL GOAL FOR PATIENTS IS TO LOSE 0.5% TO 1% INITIAL BODY WEIGHT PER WEEK—OR 5% TO 10% OF WEIGHT ACROSS SEVERAL MONTHS

• CUTTING FAT AND CALORIES. THE FIRST STEP IN LOSING WEIGHT IS TO RESTRICT HIGH-FAT AND HIGH-CALORIE FOODS AND EAT SMALLER PORTIONS. IF THIS FAILS, THEN SWITCH THE PATIENT TO A LOW- OR VERY-LOW-CALORIE DIET, WHICH PROVIDES A QUICK INITIAL WEIGHT LOSS


• EXERCISE HAS PHYSIOLOGIC AND PSYCHOLOGICAL BENEFITS, INCLUDING INHIBITING FOOD INTAKE AND PROMOTING A SENSE OF SELF-CONTROL. PHYSICAL EXERCISE INCREASES INSULIN SENSITIVITY AND REDUCES THE RISK OF SECONDARY MEDICAL PROBLEMS, SUCH AS HEART DISEASE. WALKING ≥40 MINUTES DAILY PRODUCES MAXIMAL BENEFIT, BUT WALKING EVEN 30 MINUTES 3 TIMES A WEEK CAN HELP MAINTAIN WEIGHT.

• CBT. EATING HABITS CAN BE CHANGED THROUGH IDENTIFYING LIFESTYLE BEHAVIORS TO BE MODIFIED, SETTING GOALS, MODIFYING TRIGGERS OF EXCESSIVE EATING, AND REINFORCING DESIRED BEHAVIOR WITH CBT. GRADUAL BUT CONSISTENT BEHAVIOR CHANGE LEADS TO HEALTHIER EATING HABITS, EXERCISE, AND WEIGHT LOSS. BEHAVIOR MODIFICATION ALONE CAN GENERATE A WEIGHT LOSS OF 0.5 KG TO 0.7 KG PER WEEK (UMBRICHT ET AL, 2001)


• SWITCHING. TO AVOID POLYPHARMACY, CONSIDER SWITCHING THE PATIENT TO A WEIGHT-NEUTRAL OR WEIGHT-LOSING ANTIDEPRESSANT, SUCH AS BUPROPION. KEEP IN MIND WHEN SWITCHING MEDICATIONS, HOWEVER, THAT THE NEXT AGENT WITH LESS WEIGHT-GAIN POTENTIAL MIGHT NOT DELIVER COMPARABLE ANTIDEPRESSANT EFFICACY.

• ANTIOBESITY DRUGS. SHORT OF SWITCHING, AN ANTIOBESITY DRUG OR OFF-LABEL INTERVENTION MAY BE WARRANTED. ANTIOBESITY DRUGS SHOULD NOT BE USED AS PRIMARY THERAPY FOR OBESITY.

REFERENCES• KILPATRICK, R., & WHYTE, J. H. S. (1965). SIDE-EFFECTS OF PHENOTHIAZINE DRUGS. BRITISH MEDICAL JOURNAL,

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• SERNYAK, M. J., LESLIE, D. L., ALARCON, R. D., ET AL (2002) ASSOCIATION OF DIABETES MELLITUS WITH USE OF ATYPICAL NEUROLEPTICS IN THE TREATMENT OF SCHIZOPHRENIA. AMERICAN JOURNAL OF PSYCHIATRY, 159, 561 -566.

• M. SMITH, D. HOPKINS, R. C. PEVELER, R. I. G. HOLT, M. WOODWARD, K. ISMAIL. FIRST- V. SECOND-GENERATION ANTIPSYCHOTICS AND RISK FOR DIABETES IN SCHIZOPHRENIA: SYSTEMATIC REVIEW AND META-ANALYSIS. BR J PSYCHIATRY. 2008 JUNE; 192(6): 406–411.

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• CHANGE IN METABOLIC SYNDROME PARAMETERS WITH ANTIPSYCHOTIC TREATMENT IN THE CATIE SCHIZOPHRENIA TRIAL: PROSPECTIVE DATA FROM PHASE 1. MEYER JM, DAVIS VG, GOFF DC, MCEVOY JP, NASRALLAH HA, DAVIS SM, ROSENHECK RA, DAUMIT GL, HSIAO J, SWARTZ MS, STROUP TS, LIEBERMAN JA. SCHIZOPHR RES. 2008 APR; 101(1-3):273-86.

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• PATEL, JAYENDRA K., ET AL. "METABOLIC PROFILES OF SECOND-GENERATION ANTIPSYCHOTICS IN EARLY PSYCHOSIS: FINDINGS FROM THE CAFE STUDY." SCHIZOPHRENIA RESEARCH 111.1 (2009): 9-16.

• GOFF D, SULLIVAN L, MCEVOY J, MEYER J, NASRALLAH H, DAUMIT G, LAMBERTI S, D’AGOSTINO R, STROUP T, DAVIS S, LIEBERMAN J. A COMPARISON OF TEN-YEAR CARDIAC RISK ESTIMATES IN SCHIZOPHRENIA PATIENTS FROM THE CATIE STUDY AND MATCHED CONTROLS. SCHIZOPHR RES. 2005;80(1):45. DOI: 10.1016/J.SCHRES.2005.08.010.

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• MEHRUL HASNAIN, W. VICTOR R. VIEWEG, SONJA K. FREDRICKSON, MARY BEATTY-BROOKS, ANTONY FERNANDEZ, ANAND K. PANDURANGI, CLINICAL MONITORING AND MANAGEMENT OF THE METABOLIC SYNDROME IN PATIENTS RECEIVING ATYPICAL ANTIPSYCHOTIC MEDICATIONS, PRIMARY CARE DIABETES, VOLUME 3, ISSUE 1, FEBRUARY 2009, PAGES 5-15, ISSN 1751-9918, HTTP://DX.DOI.ORG/10.1016/J.PCD.2008.10.005.

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• HTTP://WWW.CURRENTPSYCHIATRY.COM/HOME/ARTICLE/HOW-TO-CONTROL-WEIGHT-GAIN-WHEN-PRESCRIBING-ANTIDEPRESSANTS/409757C0A7B3E1E2A0ADC3D31CD13E52.HTML

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Metabolic side effects of drugs in Psychiatry

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