Is reduced dopaminergic function a forgotten factor in suicidality associated with SSRIs?
There has been much recent discussion regarding the apparent increase
in suicidality in patients treated with selective serotonin reuptake
inhibitors, particularly in early stages of treatment. Despite
difficulties in interpreting data from post-mortem tissue, there appears
to be some evidence to suggest that a reduction in dopamine turnover in
the basal ganglia is associated with suicide (Bowden et al., 1997). This
observation appears consistent with evidence that reduced activity of
dopaminergic neurons is associated with feelings of dysphoria (Voruganti
et al., 2001), whilst increases in activity lead to reward and euphoria.
Serotonergic neurons originating in the raphe nucleus modulate the
firing of dopaminergic neurons in the ventral tegmental area (VTA), the
origin of mesocorticolimbic dopaminergic projections to the nucleus
accumbens and frontal cortex. An interaction between serotonergic and
dopaminergic pathways has been proposed as a possible mechanism underlying
the therapeutic action of antidepressants (D`Aquila, et al., 2000), and an
increase in dopaminergic activity is associated with long-term
antidepressant administration (Bonhomme and Esposito, 1998). However,
electrophysiological studies in rodents have shown that acute
administration of fluoxetine and other serotonin selective reuptake
inhibitors (SSRIs), reduces the activity of dopaminergic neurons in the
VTA (Prisco and Esposito, 1995; Di Mascio et al., 1998). The authors of
these studies suggest that this may account for the akathisia sometimes
associated with SSRI therapy. However, it also seems conceivable that a
reduction in the activity of these neurons may result in suicidal thoughts
due to dysphoria and a reduction in motivation during initial treatment
with SSRIs. Following chronic fluoxetine administration (once daily
administration for twenty-one days), the reduction in dopaminergic
activity associated with acute fluoxetine challenge was lost. As neuronal
function returns to normal over a longer period of drug administration,
motivation and feelings of pleasure may return, leading to a reduction in
suicidal thoughts and improvement in affect. This may explain why the risk
of suicide associated with antidepressants is increased during early
stages of treatment, in particular during days one to nine (Jick et al.,
2004), but appears to be attenuated as treatment continues.
Bonhomme, N., Esposito, E., 1998. Involvement of serotonin and
dopamine in the mechanism of action of novel antidepressant drugs: a
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Bowden, C., Cheetham, S.C., Lowther, S., Katona, C.L.E., Crompton,
M.R., Horton, R.W. 1997. Reduced dopamine turnover in the basal ganglia of
depressed suicides. Brain Res., 769(1): 135-140.
D`Aquila, P.S., Collu, M., Gessa, G.L., Serra, G., 2000. The role of
dopamine in the mechanism of action of antidepressant drugs. Eur. J.
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Di Mascio, M., Di Giovanni, G., Di Matteo, V., Prisco, S., Esposito,
E., 1998. Selective serotonin reuptake inhibitors reduce the spontaneous
activity of dopaminergic neurons in the ventral tegmental area. Brain Res.
Bull., 46(6): 547-554.
Jick, H., Kaye, J.A., Jick, S.S., 2004. Antidepressants and the risk
of suicidal behaviours. J.A.M.A., 292(3): 379-381.
Prisco, S., Esposito, E., 1995. Differential effects of acute and
chronic fluoxetine administration on the spontaneous activity of
dopaminergic neurons in the ventral tegmental area. Br. J. Pharmacol.,
Voruganti, L., Slomka, P., Zabel, P., Costa, G., So, A., Mattar, A.,
Awad, A.G., 2001. Subjective effects of AMPT-induced dopamine depletion in
schizophrenia: Correlation between dysphoric responses and striatal D2
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Competing interests: No competing interests