Unit I herbs as raw materials, biodynamic agriculture.ppt
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
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
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• Clozapine trials performed but withdrawn in 1975 due to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
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
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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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.