metabolic side effects of drugs in psychiatry
TRANSCRIPT
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
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
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HISTORICAL PERSPECTIVE-METABOLIC SIDE EFFECTS
• 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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HISTORICAL PERSPECTIVE-METABOLIC SIDE EFFECTS
• 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
31
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
33
PATHOPHYSIOLOGY
Metabolic
Weight Gain, esp. abdominal obesity
Impaired Glucose Metabolism• Hyperglycemia• Type 2 DM
Dyslipidemia• Hyper cholesterolmia• Hypertriglyceridemia• Low HDL
34
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
40
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
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
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
51
MONITORING
Risk FactorsADA-APA
Guidelines(2004)Mount
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.
Baseline, 12 weeks and annually
Signs/Symptoms of Diabetes
BaselineBaseline and at regular intervals
Baseline and 12 weeks and annually
52
MONITORINGRisk factors ADA-APA
Guidelines(2004)Mount
Sinai Guidelines(2004)
NICE guidelines (2010)/Maudsley 2012
Hemoglobin A1C Not addressed
Recommended alternative when measurement of plasma glucose level is not feasible
Baseline, 12 weeks and annually
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
54
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
55
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
• 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
MANAGING WEIGHT GAIN
• 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)
MANAGING WEIGHT GAIN
• 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,
1(5430), 316.
• AMDISEN A. DIABETES MELLITUS AS A SIDE EFFECT OF TREATMENT WITH TRICYCLIC NEUROLEPTICS. ACTA PSYCHIATR SCAND 1964;40(SUPPL 180):411–4
• JOHNSON DA, BREEN M. WEIGHT CHANGES WITH DEPOT NEUROLEPTIC MAINTENANCE THERAPY. ACTA PSYCHIATR SCAND. 1979 MAY;59(5):525-8.
• ALLISON DB, MENTORE JL, HEO M, CHANDLER LP, CAPPELLERI JC, INFANTE MC, WEIDEN PJ. ANTIPSYCHOTIC-INDUCED WEIGHT GAIN: A COMPREHENSIVE RESEARCH SYNTHESIS. AM J PSYCHIATRY. 1999 NOV;156(11):1686-96.
• 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.
REFERENCES• DE HERT, M., SCHREURS, V., VANCAMPFORT, D. AND VAN WINKEL, R. (2009), METABOLIC SYNDROME IN PEOPLE WITH
SCHIZOPHRENIA: A REVIEW. WORLD PSYCHIATRY, 8: 15–22
• CHADDA, R. K., RAMSHANKAR, P., DEB, K. S., & SOOD, M. (2013). METABOLIC SYNDROME IN SCHIZOPHRENIA: DIFFERENCES BETWEEN ANTIPSYCHOTIC-NAÏVE AND TREATED PATIENTS. JOURNAL OF PHARMACOLOGY & PHARMACOTHERAPEUTICS, 4(3), 176–186. DOI:10.4103/0976-500X.114596
• 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.
• RUMMEL-KLUGE C, KOMOSSA K, SCHWARZ S, ET AL. HEAD-TO-HEAD COMPARISONS OF METABOLIC SIDE EFFECTS OF SECOND GENERATION ANTIPSYCHOTICS IN THE TREATMENT OF SCHIZOPHRENIA: A SYSTEMATIC REVIEW AND META-ANALYSIS. SCHIZOPHRENIA RESEARCH. 2010;123(2-3):225-233. DOI:10.1016/J.SCHRES.2010.07.012.
• 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.
REFERENCES• BOSTWICK, J. R., GUTHRIE, S. K. AND ELLINGROD, V. L. (2009), ANTIPSYCHOTIC-INDUCED HYPERPROLACTINEMIA.
PHARMACOTHERAPY, 29: 64–73. DOI: 10.1592/PHCO.29.1.64
• 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.
• GENOMEWIDE PHARMACOGENOMIC STUDY OF METABOLIC SIDE EFFECTS TO ANTIPSYCHOTIC DRUGS. ADKINS DE, ABERG K, MCCLAY JL, BUKSZÁR J, ZHAO Z, JIA P, STROUP TS, PERKINS D, MCEVOY JP, LIEBERMAN JA, SULLIVAN PF, VAN DEN OORD EJ. MOL PSYCHIATRY. 2011 MAR; 16(3):321-32.
• MARIO ÁLVAREZ-JIMÉNEZ, OBDULIA MARTÍNEZ-GARCÍA, ROCÍO PÉREZ-IGLESIAS, MARI LUZ RAMÍREZ, JOSE LUIS VÁZQUEZ-BARQUERO, BENEDICTO CRESPO-FACORRO, PREVENTION OF ANTIPSYCHOTIC-INDUCED WEIGHT GAIN WITH EARLY BEHAVIOURAL INTERVENTION IN FIRST-EPISODE PSYCHOSIS: 2-YEAR RESULTS OF A RANDOMIZED CONTROLLED TRIAL, SCHIZOPHRENIA RESEARCH, VOLUME 116, ISSUE 1, JANUARY 2010, PAGES 16-19, ISSN 0920-9964, HTTP://DX.DOI.ORG/10.1016/J.SCHRES.2009.10.012.
• CAVAZZONI, PATRIZIA, ET AL. "NIZATIDINE FOR PREVENTION OF WEIGHT GAIN WITH OLANZAPINE: A DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL." EUROPEAN NEUROPSYCHOPHARMACOLOGY 13.2 (2003): 81-85.
• PRAHARAJ, SAMIR KUMAR, ET AL. "METFORMIN FOR OLANZAPINE‐INDUCED WEIGHT GAIN: A SYSTEMATIC REVIEW AND META‐ANALYSIS." BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 71.3 (2011): 377-382.
REFERENCES• NARULA, PREETA KAUR, ET AL. "TOPIRAMATE FOR PREVENTION OF OLANZAPINE ASSOCIATED WEIGHT GAIN AND METABOLIC
DYSFUNCTION IN SCHIZOPHRENIA: A DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL." SCHIZOPHRENIA RESEARCH 118.1 (2010): 218-223.
• MUSCATELLO, M. R. A., ET AL. "TOPIRAMATE AUGMENTATION OF CLOZAPINE IN SCHIZOPHRENIA: A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY." JOURNAL OF PSYCHOPHARMACOLOGY 25.5 (2011): 667-674.
• BARNES TRE, PATON C, CAVANAGH M-R, HANCOCK E, TAYLOR DM, ON BEHALF OF THE UK PRESCRIBING OBSERVATORY FOR MENTAL HEALTH. A UK AUDIT OF SCREENING FOR THE METABOLIC SIDE EFFECTS OF ANTIPSYCHOTICS IN COMMUNITY PATIENTS. SCHIZOPHRENIA BULLETIN. 2007;33(6):1397-1403. DOI:10.1093/SCHBUL/SBM038.
• CHANGES IN WEIGHT DURING A 1-YEAR TRIAL OF FLUOXETINE.. MICHELSON D, AMSTERDAM JD, QUITKIN FM, REIMHERR FW, ROSENBAUM JF, ZAJECKA J, SUNDELL KL, KIM Y, BEASLEY CM JR. AM J PSYCHIATRY. 1999 AUG; 156(8):1170-6.
• SUSSMAN N, GINSBERG D. RETHINKING SIDE EFFECTS OF THE SELECTIVE SEROTONIN REUPTAKE INHIBITORS: SEXUAL DYSFUNCTION AND WEIGHT GAIN. PSYCHIATR ANN. 1998;28:89–97.
REFERENCES• RAEDER MB, BJELLAND I, EMIL VOLLSET S, STEEN VM. OBESITY, DYSLIPIDEMIA, AND DIABETES WITH SELECTIVE SEROTONIN
REUPTAKE INHIBITORS: THE HORDALAND HEALTH STUDY. J CLIN PSYCHIATRY. 2006 DEC;67(12):1974-82.
• BEYAZYÜZ M, ALBAYRAK Y, EĞILMEZ OB, ALBAYRAK N, BEYAZYÜZ E. RELATIONSHIP BETWEEN SSRIS AND METABOLIC SYNDROME ABNORMALITIES IN PATIENTS WITH GENERALIZED ANXIETY DISORDER: A PROSPECTIVE STUDY. PSYCHIATRY INVESTIGATION. 2013;10(2):148-154. DOI:10.4306/PI.2013.10.2.148.
• UMBRICHT D, FLURY H, BRIDLER R. COGNITIVE BEHAVIOR THERAPY FOR WEIGHT GAIN. AM J PSYCHIATRY 2001;158:971-2.
• HTTP://WWW.CURRENTPSYCHIATRY.COM/HOME/ARTICLE/HOW-TO-CONTROL-WEIGHT-GAIN-WHEN-PRESCRIBING-ANTIDEPRESSANTS/409757C0A7B3E1E2A0ADC3D31CD13E52.HTML