 The
family tree in 62-year-old Charles W's study tells a sad
story. Several of the deaths are marked 'suicide.' It
remains unfinished because Charles, once an enthusiastic
family historian, lost interest in his hobby as he, too,
was overtaken by depression. Unipolar major depression
like Charles' is heritable 40-70% of the time. A report
in the January issue of Neuron sheds some light
on this fact with the discovery of a mutation that can
cause this prevalent but poorly understood mental illness.
Depressed
mice gave the researchers their first clue. They found
that in these mice the gene producing tryptophan hydroxylase-2
— the rate-limiting enzyme in serotonin synthesis
— had a tiny little mutation. A similar mutation
was also found on the tryptophan hydroxylase-2 genes
(hTPH2) in human cell cultures. This defect causes
serotonin production to fall by an astounding 80%.
THE
HUMAN CONNECTION
The researchers screened clinically depressed and control
populations for the faulty hTPH2 gene. Nine of
87 depressed patients carried the mutated gene, which
was only present in three of 219 people in the control
population. None of the 60 bipolar patients had the
mutated gene, suggesting that this condition has other
causes.
The nine
faulty gene carriers with depression had little or no
symptom relief with selective serotonin re-uptake inhibitor
(SSRI) therapy. This startling finding could lead to
a diagnostic test to help doctors select more effective
treatments for their depressed patients.
If that
isn't enough, it also appears that mental illness can
be inherited along with the defective gene. Ten of the
12 carriers identified in the study had family histories
of mental illness, and/or drug and alcohol abuse.
"This
is a major finding with implications not only for understanding
the cause and development of depression, but also its
treatment and management," said investigator Dr K Ranga
Krishnan of Duke University.
The researchers
hope to screen a larger population to confirm the link
between unipolar depression and the faulty hTPH-2
gene. They also plan to investigate whether this mutation
contributes to other mental illnesses such as generalized
anxiety disorder, schizophrenia, suicide, autism, attention
deficit hyperactivity disorder and drug abuse.
Neuron
2005 Jan 6;45:11-6
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