Role of 5-HT_2C receptor gene variants in antipsychotic-induced weight gain

Figures & data

Table 1 Summary of genetic studies associating the single nucleotide polymorphism −759C/T with antipsychotic-induced weight gain

Duration	Medication (N)	N (f)	Ethnicity	History (in-/outpatient)	Measure	Main finding	Ref
4 mo	Clozapine	80 (28)	Han Chinese	Treatment resistant	> or <7% weight change	NS	^Citation33
6–14 wk (avg 11.2)	Clozapine (92), Olanzapine (21), Haloperidol (13), Risperidone (13)	139 (NR)	African-American and European ancestry	Chronic	> or <7% weight change	NS	^Citation29
6 wk	Olanzapine	42 (8)	European ancestry	NA (inpatient)	> or <5%, 7%, 10% weight change	T protective against 10% weight gain (P = 0.0035)	^Citation21
6 wk	Olanzapine	107 (54)	European ancestry (Polish origin)	Atypical naïve with 36 drug naïve (inpatient)	> or <7% and 10% BMI change	T protective against 10% BMI change (P = 0.002); still significant in 36 drug-naïve patients (P = 0.05)	^Citation22
6 mo	Clozapine	41 (15)	European ancestry (35), African-American (5), Hispanic (1)	Refractory	> or <7% BMI change	T protective (P = 0.0026); in European ancestry S alone (P = 0.0052)	^Citation25
6 and 10 wk	Chlorpromazine (49), Risperidone (46), Clozapine (8), Other (4)	123 (62)	Han Chinese	First episode (inpatients)	Change in BMI	Wild type (CC) with greater BMI increase at 6 (P < 0.0001) and 10 wk (P < 0.0003)	^Citation26
6 wk, 3, and 9 mo	Majority Olanzapine or Risperidone	75 (18)	European ancestry	First episode	Change in BMI	Variant protective at 6 wk, 3, and 9 mo (P = 0.003, 0.018, 0.031, respectively)	^Citation28
<42 d	Risperidone	123 (55)	Han Chinese	No atypical (inpatients)	Weight gain (kg) adjusted for baseline	Variant (C/T or T/T in women, T in men) protective (P = 0.04)	^Citation23
NA	Clozapine (44), Olanzapine (40), Risperidone (26), Other (26)	127 (47)	>95% European ancestry	Chronic (majority outpatients)	Obesity	NS	^Citation31
6 wk	Olanzapine (33), Clozapine (24), Risperidone (8), Combination (52)	128 (48)	Eastern European (8), Western European (110), Turkish (10)	Mixed (both)	> or <7% weight change	C associated with weight gain (P = 0.04)	^Citation24
>3 mo	Olanzapine	79 (26)	Korean	No clozapine or olanzapine treatment, majority chronic	> or <7% weight change	NS	^Citation32
8–24 wk	Olanzapine	164 (64)	Japanese	Most with previous treatment (inpatients)	% BMI change	NS	^Citation34
4 wk	Risperidone (53), Olanzapine (12), Amisulpride (5), Quetiapine (4), Typical (10)	84 (45)	Korean	Treatment free for 3 mo (inpatients)	> or <5% and 7% weight change	T less likely in 5% (P = 0.03) and 7% (P = 0.048)	^Citation27
4 mo	Olanzapine (61), Risperidone (42)	108 (108)	Croatian	Majority antipsychotic naïve (outpatient)	> or <5% weight change	NS	^Citation30
NA	Oral: Olanzapine (31), Clozapine (21), Risperidone (16), Depot (27), Other (37), None (2)	134 (47)	NA	NA (outpatient)	Obesity and metabolic syndrome	NS	^Citation35

Abbreviations: avg, average; BMI, body mass index; d, day; f, female; mo, month; N, number of patients; NA, not available; NR, not reported; NS, not statistically significant; Ref, reference; wk, week.

Table 2 Breakdown of studies investigating −759C/T based on characteristics of the patient population

Variable	Category	Statistically significant	Not statistically significant
Treatment duration	<2 mo	[21] [22] [23] [24] [26] [27] [28]	[29]
	≥2 mo	[25] [28]	[30] [32] [33] [34]
Medication	Majority high risk^a	[21] [22] [24] [25] [28]	[29] [30] [31] [32] [33] [34] [35]
	Majority not high risk	[23] [26] [27]	NA
Ethnicity	Chinese	[23] [26]	[33]
	Korean	[27]	[32]
	Japanese	NA	[34]
	European ancestry	[21] [22] [24] [25] [28]	[30] [31]
	African ancestry mixed with European ancestry	NA	[29]
Treatment history	Atypical naïve, antipsychotic naïve, or first episode	[22] [23] [26] [28]	[30]
	Chronic/treatment resistant	[25]	[29] [31] [33]
Environmental factors	Inpatients	[21] [22] [23] [26] [27]	[34]
	Outpatients	NA	[30] [31] [35]

Note:

a Clozapine or olanzapine.

Abbreviations: mo, month; NA, not applicable.

Table 3 Summary of genetic studies associating the single nucleotide polymorphism −697C/G with antipsychotic-induced weight gain

Duration	Medication	N (f)	Ethnicity	History (in-/outpatient)	Measure	Main finding	Ref
NA	Clozapine (44), Olanzapine (40), Risperidone (26), Other (26)	127 (47)	>95% European ancestry	Chronic (majority outpatients)	Obesity	NS	^Citation31
6 wk	Olanzapine	107 (54)	European ancestry	Atypical naïve with 36 drug naïve, not treatment resistant (inpatient)	> or <7% and 10% BMI change	C protective against 10% BMI change (P < 0.001); still significant in 36 drug-naïve patients (P = 0.008).	^Citation22

Abbreviations: BMI, body mass index; f, female; NA, not available; NS, not statistically significant; Ref, reference; wk, week.

Table 4 Summary of genetic studies associating the single nucleotide polymorphism Cys23Ser with antipsychotic-induced weight gain

Duration	Medication	N (f)	Ethnicity	History (in-/outpatient)	Measure	Main finding	Ref
6–14 wk (avg 11.2)	Clozapine (92), Olanzapine (21), Haloperidol (13), Risperidone (13)	139 (NR)	African-American and European ancestry	Chronic	> or <7% weight change	NS	^Citation29
69.8 (±40) wk	Clozapine	152 (76)	German descent	All with previous treatment, majority treatment resistant	% change in weight	NS	^Citation49
<42 d	Risperidone	123 (55)	Han Chinese	No atypical (inpatients)	Weight gain (kg) adjusted for baseline	Minor allele not observed	^Citation23
6 wk	Clozapine (24), Olanzapine (33), Risperidone (8), Combination (52)	128 (48)	Eastern European (8), Western European (110), Turkish (10)	Mixed (both)	> or <7% weight change	NS	^Citation24
4 wk	Olanzapine (35), Risperidone (32), Amisulpride (22), Quetiapine (16), Clozapine (16), Ziprasidone (9), Other typical (50)	102 (56)	European ancestry	48% with previous treatment (inpatients)	Change in BMI	NS	^Citation50
8–24 wk	Olanzapine	164 (64)	Japanese	NA (inpatients)	% BMI change	Ser23 a risk factor in stepwise linear regression, but not associated with change in BMI	^Citation34
4 mo	Clozapine	93 (33)	Chinese	Treatment refractory	Weight change	NS	^Citation51
6 wk	Clozapine	80 (28)	European ancestry (58), African-American (22)	NA	Weight change	NS	^Citation52

Abbreviations: avg, average; BMI, body mass index; d, day; f, female; mo, month; NA, not available; NR, not reported; NS, not statistically significant; Ref, reference; wk, week.

Table 5 Summary of genetic studies associating other single nucleotide polymorphisms (SNPs) with antipsychotic-induced weight gain

SNP	Duration	Medication	N (f)	Ethnicity	History (in-/outpatient)	Measure	Main finding	Ref
−997G/A	NA	Clozapine (44), Olanzapine (40), Risperidone (26), Other (26)	127 (47)	>95% European ancestry	Chronic (majority outpatients)	Obesity	NS	^Citation31
−997G/A	6 wk	Olanzapine (33), Clozapine (24), Risperidone (8), Amisulpride (2), Quetiapine (2), Combination (52)	128 (48)	Eastern European (8), Western European (110), Turkish (10)	Mixed (both)	> or <than 7% weight change	Associated with weight gain in haploview (P = 0.038)	^Citation24
rs1414334	NA	Clozapine (44), Olanzapine (40), Risperidone (26), Other (26)	127 (47)	>95% European ancestry	Chronic (majority outpatients)	Obesity	C associated OR 2.8; 95% CI: 1.03–7.62	^Citation31
−1165 A/G	6 wk	Olanzapine (33), Clozapine (24), Risperidone (8), Amisulpride (2), Quetiapine (2), Combination (52)	128 (48)	Eastern European (8), Western European (110), Turkish (10)	Mixed (both)	> or <7% weight change	A/AA associated with weight gain (P = 0.052) in haploview (P = 0.0049)	^Citation24
[(GT)12–18/(CT) 4–5] repeat	6–14 wk (avg 11.2)	Clozapine (92), Olanzapine (21), Other (26)	139	African-American	Chronic	> or <7% weight change	NS	^Citation29
c.1-142948(GT)n (13 or 16 repeat)	NA	Clozapine (44), Olanzapine (40), Risperidone (26), Other (26)	127 (47)	>95% European ancestry	Chronic (majority outpatients)	Obesity	NS	^Citation31

Abbreviations: avg, average; CI, confidence interval; f, female; NA, not available; NS, not statistically significant; OR, odds ratio; Ref, reference; wk, week.

Table 6 Summary of genetic studies associating haplotypes with antipsychotic-induced weight gain

SNPs	Duration	Medication	N (f)	Ethnicity	History (in-/outpatient)	Measure	Main finding	Ref
−759C/T, Cys23Ser repeat	6–14 wk (avg 11.2)	Clozapine (92), Olanzapine (21), Other (26)	139 (NR)	African-American and European ancestry	Chronic	% weight change	Long-C-Ser (n = 13) increased weight (P = 0.042)	^Citation29
Cys23Ser, −759C/T, −697C/G	>6 mo	Olanzapine (28), Clozapine (18)	46 (20)	European ancestry	Majority with previous atypical treatment (outpatient)	BMI	Higher BMI in C-C-Ser (P = 0.029); C-G-Cys over-represented in obese patients (P = 0.015)	^Citation39
−1165 A/G, −997G/A, −759C/T	6 wk	Clozapine (24), Olanzapine (33), Risperidone (8), Amisulpride (2), Quetiapine (2), Combination (52)	128 (48)	Eastern European (8), Western European (110), Turkish (10)	Mixed (both)	> or <7% weight change	A-G-C over-represented in cases (P = 0.0049)	^Citation24
−759C/T, −697C/G	6 wk	Olanzapine	107 (54)	European ancestry	Atypical naïve with 36 drug naïve, not treatment resistant (inpatient)	> or <7% and 10% BMI change	Haplotypes associated with >10% change in BMI (P = 0.001)	^Citation22

Abbreviations: avg, average; BMI, body mass index; f, female; mo, month; NR, not reported; Ref, reference; SNP, single nucleotide polymorphism; wk, week.

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