Serotonin and aggression, panic attack and related disorders

Serotonin and aggression, panic attack and related disorders
The possible overlap between anxiety, depression, panic attack, aggression
and obsessive–compulsive disorders, and the involvement of serotonin in
the symptoms of these disorders, has recently led to the investigation of
various selective serotonin reuptake inhibitors (SSRIs) and selective 5-HT
receptor agonists/antagonists in the treatment of these conditions. In
experimental studies, there is evidence that drugs such as eltoprazine,
which binds with high affinity to 5-HT1A, 5-HT1B and 5-HT2C sites, are
active antiaggressive agents, whereas selective 5-HT1A agonists and 5-HT2
and 5-HT3 antagonists are inactive. There is also preliminary evidence to
suggest that SSRIs such as fluoxetine reduce impulsive behaviour which
may contribute to their therapeutic action in the treatment of obsessive–
compulsive disorders and possibly in reducing suicidal attempts.
Zohar and Insel have suggested that the symptoms of obsessive–
compulsive disorder are due to supersensitive 5-HT1-type receptors and
that the function of SSRIs such as clomipramine, fluoxetine and the
non-selective 5-HT antagonist metergoline owe their efficacy to their ability
to reduce the activity of these receptors.
It now seems generally accepted that the effects of anti-obsessional drugs
may be mediated by serotonergic mechanisms. The apparent hypersensitivity
of obsessive–compulsive patients to the trazodone metabolite m-chlorophenyl
piperazine (mCPP, a non-selective 5-HT1B, 5-HT2C and 5-HT2 agonist)
suggests that a diverse group of 5-HT1 and 5-HT2 receptors are involved.
The efficacy of buspirone, a partial agonist of 5-HT1A receptors, in
attenuating the obsessional symptoms further suggests that 5-HT1A
receptors are also involved. As the 5-HT reuptake inhibitors such as
fluoxetine and fluvoxamine are particularly effective in attenuating the
obsessive symptoms following several weeks of administration, it may be
argued that the therapeutic effect of such drugs lies in their ability to
desensitize the supersensitive 5-HT1-type receptors. Which of the 5-HT1
receptors is specifically involved is unclear, but neuroimaging studies on
patients with obsessive–compulsive disorder implicate the striatum as the
major brain region which is defective. The 5-HT receptors in the striatum
are 5-HT1D and 5-HT2 in man which may implicate these receptor subtypes
specifically in the aetiology of the condition.
With regard to generalized anxiety disorder, it has been postulated that
an overactivity of the stimulatory 5-HT pathways occurs. Drugs such as
buspirone and ipsapirone are effective in such conditions because they
stimulate the inhibitory 5-HT1A autoreceptors on the raphe´ nuclei and
thereby reduce serotonergic function. It is noteworthy that the SSRIs often
worsen anxiety initially because they temporarily enhance serotonergic
function. Adaptive changes in the pre- and postsynaptic 5-HT receptors
then occur leading to a reduction in the anxiety state.