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Serotonin Genes and Suicidal Behavior in Schizophrenia

Reviews conclude that the strongest current evidence for a genetic role in suicidal behavior

lies with 2 serotonin genes: tryptophan hydroxylase and the serotonin transporter.[110] , [111]

Tryptophan hydroxylase (TPH 2) in relation to suicidal behavior

TPH is the rate-limiting enzyme in the synthesis of serotonin, a neurotransmitter implicated

in suicidal behavior. TPH2 has been implicated in both completed suicide and attempted

suicide.[112] , [113]

For example, in the authors' study Zhou and colleagues[114]examined different markers in the

5-promoter and 3-untranslated regions, and 15 SNPs spanning 106 kbp of the TPH2 gene in

1798 cases and controls. The authors reported a haplotype block of 52 kbp in size, which was

associated with an increased risk of making a suicide attempt. However, there has been a

negative report in schizophrenic suicides.[115]

Serotonin transporter (5-HTT) and attempting suicide

The 5-HTT proteins are responsible for the reuptake of synaptic serotonin. In a review, Lin

and Tsai[111]concluded that genotypes carrying the short (s) allele of the 5-HTTLPR gene

were found significantly more among patients attempting suicide than among patients who

had never attempted. There was also a significant association between the SS+LS genotype

and suicide attempts (P= .003). The frequency of the s allele was significantly higher in

violent attempters, reattempters, or completers (P= .033). De Luca and colleagues[115]found

that the intron 2-VNTR polymorphism of the 5-HTT gene was significantly associated with

attempting suicide among 290 schizophrenics.

5-HTTLPR/life event interaction, and depression and suicidality

Depression is associated with suicidal behavior in schizophrenic patients, and is often

precipitated by life events. Thus it is relevant that Caspi and colleagues[116]showed that the 5-

HTT gene predicted an individual's sensitivity to the stressful life events precipitating

depression. This group reported that an interaction between polymorphism of the 5-HTTLPR

gene and stressful recent life events predicted depression and suicidal ideation and attempts

in young adults with an s allele but not in l/l homozygotes. Others reported similarly in

relation to depression (reviewed in Uher and McGuffin[117]). Caspi and colleagues[116]and the

authors[118]

also reported that 5-HTTLPR polymorphism interacted with childhood trauma toprecipitate depression and suicide attempts. Particularly relevant is a recent report that in

psychotic patients the ss or sl genotype of the 5-HTTLPR gene increased the risk of

developing major depression during the course of their illness.[119]

Serotonin 2C receptor and suicide in schizophrenia

Dracheva and colleagues[120]recently reported a postmortem genetic study of schizophrenicand bipolar suicide victims and found 5-HT2CR mRNA editing variations that were

associated with the suicides compared with controls. These investigators noted that because

the VSV isoform of 5-HT2CR exhibits low functional activity, an increase in its expression

frequency may significantly influence serotonin in the brain. Dracheva and colleagues

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concluded that overexpression of the VSV isoform in the prefrontal cortex may represent an

additional risk factor for suicidal behavior in schizophrenia.