Genomic Keys to Depression Could Unlock Antidepressant Response

March 1, 2005

Three recently published studies uncovered some answers to the genetic underpinnings of depression. Familial vulnerability was shown to increase with each generation affected by depression. Two genetic variants pointed in opposite directions: one showed an increase risk of depression and the other predicted responsiveness to antidepressants.

Psychiatric Times

February 2005

Vol. XXII

Issue 3

As a three-generation study was published with new evidence that major depression can afflict families from one generation to the next, genomic research reported associated heightened risk for depression and specific treatment response with particular genotypes. The 20-year longitudinal family study found twice the rate of depression or anxiety in children whose parents and grandparents also had depression than in children without such a history (Arch Gen Psychiatry 2005;62[1]:29A-36). Two other recent publications offered examples of mechanisms for such familial vulnerability: In one, a defect in a gene that codes the enzyme tryptophan hydroxylase-2, integral to serotonin synthesis, was linked to depression risk (Neuron 2005;45[1]:11-16). In another, a variant in the corticotropin-releasing hormone (CRH) receptor 1 (CRHR1) gene predicted responsiveness to antidepressants (Mol Psychiatry 2004;9[12]:1075-1082).

Generational Risk

The longitudinal family study, conducted by Myrna M. Weissman, Ph.D., and colleagues, not only supports numerous other studies of depression risk in offspring of parents with major depression disorder, but finds the risk carried through several generations and suggests that it intensifies as more are affected (Arch Gen Psychiatry 2005;62[1]:29A-36). The researchers found 59.2% of the children of an afflicted parent and grandparent had a psychiatric disorder, most frequently anxiety, at the group's mean age of 12 years. They extrapolated from other data to consider the anxiety disorder at this age to be a precursor of depression in adolescence and young adulthood.

Weissman and colleagues reported that the effect of parental depression on the outcomes of children differs significantly with grandparent depression status. Children with a depressed grandparent and parent had an increased risk of an anxiety disorder (relative risk=5.17) and of any psychiatric disorder (relative risk=5.52), compared with children who had a depressed grandparent but nondepressed parents. The severity of parental depression in terms of impairment significantly increased the rate of a mood disorder in those grandchildren. In contrast, there was no significant effect of parental depressive disorder without grandparent depression on the diagnosis of grandchildren; although parental depression did affect overall functioning of their children.

"The development of depression in a young person may be conditional on both a parent and a grandparent having a moderate to severe depression," Weissman and colleagues posited, adding, "These effects may be independent of environmental confounders."

Noting that their study was not designed to gather genomic data, Weissman and colleagues observed, "Whether these generations also carry [a] functional polymorphism is an interesting, unanswered question."

Implicating Genetic Mutation

Two other reports provided evidence that a functional polymorphism can underlie familial patterns of major depression, as well as responsiveness to antidepressant treatment. Xiaodong Zhang, Ph.D., and colleagues discovered a mutation of the gene coding hydroxylase-2 that results in an approximate 80% reduction in the neurotransmitter serotonin (Neuron 2005;45[1]:11-16).

The mutant gene interfering with serotonin synthesis was found in nine of 87 patients with depression, compared to three of 219 healthy controls and none of 60 patients with bipolar disorder. Among the nine patients carrying the mutant gene, seven had a family history of mental illness or substance abuse, six had been suicidal, and four had symptoms of an anxiety disorder. In addition, seven of the nine had been unresponsive to serotonin selective antidepressants, and the other two had responded only at high doses.

Although this is the first functional single nucleotide polymorphism (SNP) found in the gene coding human tryptophan hydroxylase-2, Zhang and colleagues anticipated that others could be found for the same gene. They noted that more than 400 mutations have been found for a gene coding the closely related phenylalanine hydroxylase, which causes varying degrees of hyperphenylalaninemia.

Zhang and colleagues called for larger studies to confirm their findings and investigate further the inheritance and penetrance of this SNP in major depression. "It will also be of interest," they commented, "to test how this mutation may interact with other genetic alterations previously associated with depression."

Julio Licinio, M.D., from the Center for Pharmacogenomics and Clinical Pharmacology at the Neuropsychiatric Institute of the University of California, Los Angeles, and colleagues reported that individuals with high levels of depression and anxiety are more responsive to antidepressant medication if they carry a particular variant of the CRHR1 gene (Mol Psychiatry 2004;9[12]:1075-1082).

Their sample of 80 patients with depression were classified as having high or low anxiety and were treated with fluoxetine (Prozac) or desipramine (Norpramin) in double-blind format. In those with high levels of anxiety and depression, homozygosity for one of four haplotypes of CRHR1 was associated with a 70% greater reduction in Hamilton Rating Scale for Anxiety (HAM-A) scores and 31% greater reduction in Hamilton Rating Scale for Depression (HAM-D) scores with either antidepressant compared to patients with similar symptom levels who were heterozygous for the haplotype. No association was found, however, between CRHR1 genotype and treatment response in patients with lower levels of symptom severity.

"The findings reported here represent a new line of evidence that further strengthen the concept that CRH has a role in depression and that CRHR1 is involved in antidepressant response," Licinio and colleagues commented.

Pharmacogenomic researchers are pursuing the possibility that there are common mechanisms for antidepressant effect that are activated after chronic treatment with monoaminergic drugs. Licinio and colleagues posited that the CRHR1 gene is part of such a mechanism, which could lead to CRH receptor antagonist antidepressant medications. "Importantly, these findings suggest that specific variants of the CRHR1 gene may influence the efficacy of CRHR1 agonists or antagonists," they remarked.

A genomic pathway to manifestations of depression or mechanisms of antidepressant effect, however, will be circuitous and splintered, and unlikely to encompass the disorder. In reflecting on their study of three generations, Weissman and colleagues offered this caution to researchers: "Because parents may provide both high-risk genes and a high-risk rearing environment, disentangling psychosocial and biological factors mediating the transmission of risk across generations is a challenge."