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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
Metabolic side effects of drugs in Psychiatry
Metabolic side effects of drugs in Psychiatry
Metabolic side effects of drugs in Psychiatry
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 <40
Female <50
Male <40
Female <50
Male <40
Female <50
Triglycerides(mg/dl
)
≥150 ≥150 ≥150
Glucose(mg/dl) ≥110 ≥100 ≥100
Hert et al, 2009
8
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
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
12
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 receptors
Histamine, muscarinic,
adrenergic
13
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)
14
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
15
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
16
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
17
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
18
ANTIPSYCHOTICS AND DIABETES
• PERCENTAGE OF PATIENTS WITH SCHIZOPHRENIA RECEIVING ATYPICAL
AND TYPICAL NEUROLEPTIC MEDICATION WITH DIABETES MELLITUS
Sernyak et
al,2002
19
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
20
METABOLIC SYNDROME
Study 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,
21
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 PRESSURE
22
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 23
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, 201024
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(≥7k
g)
Metabolic
syndrome (n=52 at
52 weeks)
Olanzapin
e
2.5-20 59.8% 80% 22 (42.3%)
Quetiapin
e
100-800 29.2% 50% 18(34.6%)
Risperidon
e
0.5-4 32.5% 57.6% 11(21.15%) 25
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 CONTROLSCATIE 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
26
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
27
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 FGA
104
olanzapine
Risperidone
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 -
204
Haloperidol
104
Placebo 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
group
No change in placebo
First-generation antipsychotics, Risperidone,
Paliperidone >Ziprasidone > olanzapine >
Quetiapine, clozapine> Aripiprazole
28
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
29
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
30
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
31
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
32
PATHOPHYSIOLOGY
Metabolic
Weight Gain, esp.
abdominal obesity
Impaired Glucose
Metabolism
• Hyperglycemia
• Type 2 DM
Dyslipidemia
• Hyper
cholesterolmia
• Hypertriglyceride
Cardiovascular
Arterial
Hypertension
Disorder of Heart
and Blood Vessels
, Atherosclerosis
Sudden cardiac
death,
Myocarditis
33
FACTORS AFFECTING SIDE EFFECTS
• Long term treatment
• Polypharmacy
• High dosage
• Type of medications
• History of prior
treatment
• Episode of illness
• Cannabis use
• Smoking
• BMI
• Negative Symptoms
• ethnicity
• Family
History of
obesity
• Parental BMI
• Genetic
Factors FAMILIAL PERSONAL
TREATMENTILLNESS
Hasnain et al, 2008
34
FACTORS AFFECTING SIDE
EFFECTS
Diabetes
Dyslipidemi
a
Metabolic
Syndrome
Vascular
Inflammatio
n and Hyper
-
coagulation
Increased
Mortality and
Morbidity
35
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
36
Metabolic side effects of drugs in Psychiatry
Metabolic side effects of drugs in Psychiatry
Metabolic side effects of drugs in Psychiatry
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. 201040
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
EARLY BEHAVIOURAL
INTERVENTION
J Clin Psychiatry. 2006Jimenez et al,2006
42
SWITCHING OF ANTIPSYCHOTICS
STUDY SAMPL
E SIZE
SHIFT RESULTS PSYCHOP
ATHOLOG
Y
Newcomer et
al. 2008
Multicentric
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 risperidone
to Aripiprazole
Remained on the same
Significant weight
reductions and
an 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
43
SWITCHING OF ANTIPSYCHOTICS
44
Buckley et al, 2008
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
45
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
metformin
The adverse
events reported
with 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,
46
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
47
Metabolic side effects of drugs in Psychiatry
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 glucose
intolerance
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.
Dyslipidemia
Consider change to lower risk
medication. May consider specialist
referral.
Dietary advice to reduce fat
intake.
Pharmacologic intervention with
a lipid-lowering agent.
49
MONITORING
Risk 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 50
MONITORING
Risk Factors
ADA-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
EKG Baseline and annually
Baseline. Subsequent
EKG if symptoms
present.
Baseline, 12 weeks and annually
Signs/Symptoms
of Diabetes
Baseline
Baseline and at regular
intervals
Baseline and 12 weeks and annually
51
MONITORING
Risk 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
52
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, 200953
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
54
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 55
ANTIDEPRESSANT DRUGS
Metabolic side effects of drugs in Psychiatry
• 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.
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
62
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 FUNCTION.
• BUPROPION MAXIMIZES NOREPINEPHRINE AND DOPAMINE, AND HAS
ALMOST NO HISTAMINE OR ANTICHOLINERGIC EFFECT AT ALL AND SO IT CAUSES
63
Metabolic side effects of drugs in Psychiatry
Metabolic side effects of drugs in Psychiatry
Metabolic side effects of drugs in Psychiatry
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.
Metabolic side effects of drugs in Psychiatry
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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
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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
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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,
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JL, BUKSZÁR J, ZHAO Z, JIA P, STROUP TS, PERKINS D, MCEVOY JP, LIEBERMAN JA, SULLIVAN PF, VAN DEN OORD EJ. MOL PSYCHIATRY.
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• 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
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THANK YOU

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Metabolic side effects of drugs in Psychiatry

  • 1. METABOLIC SIDE EFFECTS OF DRUGS IN PSYCHIATRY PRESENTER – DR. SRIRAM.R, PG MD PSYCHIATRY CHAIRPERSON – DR. ARUL, ASSISTANT PROF OF PSYCHIATRY
  • 2. 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
  • 3. ORGANISATION • ANTIDEPRESSANT DRUGS • CLASSIFICATION • SSRI AND WEIGHT GAIN • PATHOPHYSIOLOGY OF WEIGHT GAIN • MANAGING WEIGHT GAIN • REFERENCES
  • 4. 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
  • 8. 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 <40 Female <50 Male <40 Female <50 Male <40 Female <50 Triglycerides(mg/dl ) ≥150 ≥150 ≥150 Glucose(mg/dl) ≥110 ≥100 ≥100 Hert et al, 2009 8
  • 10. 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
  • 11. • 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
  • 12. 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 12
  • 13. 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 receptors Histamine, muscarinic, adrenergic 13
  • 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) 14
  • 15. 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 15
  • 16. 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 16
  • 17. 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 17
  • 18. 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 18
  • 19. ANTIPSYCHOTICS AND DIABETES • PERCENTAGE OF PATIENTS WITH SCHIZOPHRENIA RECEIVING ATYPICAL AND TYPICAL NEUROLEPTIC MEDICATION WITH DIABETES MELLITUS Sernyak et al,2002 19
  • 20. 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 20
  • 21. METABOLIC SYNDROME Study 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, 21
  • 22. 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 PRESSURE 22
  • 23. 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 23
  • 24. 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, 201024
  • 25. 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(≥7k g) Metabolic syndrome (n=52 at 52 weeks) Olanzapin e 2.5-20 59.8% 80% 22 (42.3%) Quetiapin e 100-800 29.2% 50% 18(34.6%) Risperidon e 0.5-4 32.5% 57.6% 11(21.15%) 25
  • 26. 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 CONTROLSCATIE 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 26
  • 27. 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 27
  • 28. 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 FGA 104 olanzapine Risperidone 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 - 204 Haloperidol 104 Placebo 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 group No change in placebo First-generation antipsychotics, Risperidone, Paliperidone >Ziprasidone > olanzapine > Quetiapine, clozapine> Aripiprazole 28
  • 29. 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 29
  • 30. 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 30
  • 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 31
  • 32. 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 32
  • 33. PATHOPHYSIOLOGY Metabolic Weight Gain, esp. abdominal obesity Impaired Glucose Metabolism • Hyperglycemia • Type 2 DM Dyslipidemia • Hyper cholesterolmia • Hypertriglyceride Cardiovascular Arterial Hypertension Disorder of Heart and Blood Vessels , Atherosclerosis Sudden cardiac death, Myocarditis 33
  • 34. FACTORS AFFECTING SIDE EFFECTS • Long term treatment • Polypharmacy • High dosage • Type of medications • History of prior treatment • Episode of illness • Cannabis use • Smoking • BMI • Negative Symptoms • ethnicity • Family History of obesity • Parental BMI • Genetic Factors FAMILIAL PERSONAL TREATMENTILLNESS Hasnain et al, 2008 34
  • 35. FACTORS AFFECTING SIDE EFFECTS Diabetes Dyslipidemi a Metabolic Syndrome Vascular Inflammatio n and Hyper - coagulation Increased Mortality and Morbidity 35
  • 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 36
  • 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. 201040
  • 41. 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. 2006Jimenez et al,2006 42
  • 43. SWITCHING OF ANTIPSYCHOTICS STUDY SAMPL E SIZE SHIFT RESULTS PSYCHOP ATHOLOG Y Newcomer et al. 2008 Multicentric 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 risperidone to Aripiprazole Remained on the same Significant weight reductions and an 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 43
  • 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 45
  • 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 metformin The adverse events reported with 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, 46
  • 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 47
  • 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 glucose intolerance 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. Dyslipidemia Consider change to lower risk medication. May consider specialist referral. Dietary advice to reduce fat intake. Pharmacologic intervention with a lipid-lowering agent. 49
  • 50. MONITORING Risk 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 50
  • 51. MONITORING Risk Factors ADA-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 EKG Baseline and annually Baseline. Subsequent EKG if symptoms present. Baseline, 12 weeks and annually Signs/Symptoms of Diabetes Baseline Baseline and at regular intervals Baseline and 12 weeks and annually 51
  • 52. MONITORING Risk 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 52
  • 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, 200953
  • 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 54
  • 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 55
  • 58. • 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)
  • 59. 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
  • 60. 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.
  • 61. 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 62
  • 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 FUNCTION. • BUPROPION MAXIMIZES NOREPINEPHRINE AND DOPAMINE, AND HAS ALMOST NO HISTAMINE OR ANTICHOLINERGIC EFFECT AT ALL AND SO IT CAUSES 63
  • 67. 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
  • 68. 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)
  • 69. 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.
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Notas del editor

  1. Reference
  2. J Clin Psy 2008;69(Suppl 1):4-17
  3. As stated in the 2010 PORT guidelines (Buchanan et al. 2010) and in a review from the schizophrenia research group (Faulkner et al. 2007b), a general recommendation for a drug intervention to reduce antipsychoticinduced weight gain cannot be given. Furthermore, the aspect of worsening psychosis after adding one or two other agents to the present antipsychotic medication needs to be addressed in future studies. However, as discussed above and in the fi rst part of these updated guidelines, a switch from one antipsychotic with an unfavourable metabolic profi le to one with a better profi le (e.g., aripiprazole, ziprasidone) might be a promising therapeutic alternative.