P1vital
CNS Experimental Medicine : DEPRESSION
Background
The World Health Organization describes major depression
as the leading cause of disability worldwide among persons aged
5 years and older, affecting about 340 million people worldwide.
It is the most common and widespread of all psychiatric disorders,
and it takes a significant toll on individuals, families, and society.
Depression also negatively affects the economy through diminished
productivity and use of healthcare resources. Nearly twice as many
women (12%) as men (7%) are affected by a depressive disorder each
year. The number of prescriptions written for depressive episodes
peaks in the US for patients in the 45-49 age range. Antidepressants
are widely used as effective treatments for depression. Existing
antidepressants influence the functioning of the neurotransmitters
serotonin, noradrenaline and dopamine. Although some improvements
may be seen in the first few weeks, antidepressants generally need
to be taken for three to four weeks (in some cases, eight weeks)
before the therapeutic effect occurs. Patients often are tempted
to stop medication too soon and side effects may appear before antidepressant
activity. Newer medications, such as the selective serotonin reuptake
inhibitors (SSRIs), tend to have fewer side effects than the older
drugs, which include tricyclic antidepressants and monamine oxidase
inhibitors. Nevertheless, there is a need for a more rapidly acting
antidepressant which does not have the side-effect limitations of
current therapies, for example sexual dysfunction and nausea. The
recent history of novel antidepressant drug development is of expensive
failures in late stage trials. Hence, there is considerable potential
for Experimental Medicine models to be used to select the best compounds
for late stage trials.
Emotional processing
& Facial recognition
|
|
Although
it is well established that antidepressants that increase
serotonin or noradrenaline in the brain are effective in treating
depression, there is no neuropsychological account of how
these changes relieve depressive states. Researchers in Oxford
led by Prof Guy Goodwin have shown that seven days administration
of the SSRI citalopram (20 mg, PO) effects emotional processing
in a selective manner that may be relevant to its mechanism
of action. Subjects completed a facial expression recognition
task following citalopram or placebo (between-subjects design,
double-blind). Facial expressions associated with five basic
emotions: happiness, sadness, fearfulness, anger and disgust
were displayed. Each face had been 'morphed' between neutral
(0%) and each emotional standard (100%) in 10% steps, leading
to a range of emotional intensities. Volunteers receiving
citalopram gave lower intensity ratings to facial expressions
of fear, relative to the rating given by those receiving placebo.
Citalopram did not affect ratings of ‘happy’ per
se but it did induce a ‘happy’ bias that is volunteers
falsely labeled negative facial expressions as happy. Notable
differences in overt mood were also not apparent in these
volunteers. When citalopram (10 mg IV) was infused acutely
it increased the detection of fear and happy faces. These
results suggest that short-term administration of antidepressant
drugs may affect neural processes involved in the processing
of social information. These effects may represent an early
action of SSRIs on social and emotional processing that is
relevant to their therapeutic mechanism. The advantage of
this model is that putative antidepressants can potentially
be assessed in normal volunteers in a relatively short period
of time.
|
|
|
|
|
|
Pharmacological fMRI
|
Changes in serotoninergic neurotransmission have been
implicated in the etiology and treatment of impulse control disorders, depression, and anxiety.
Researchers in Manchester led by Prof Bill Deakin have investigated the effect of enhancing
serotonin function on fundamental brain processes that may be abnormal in these disorders.
Male volunteers received citalopram (7.5 mg intravenously) and placebo pretreatment in a single-blind crossover
design before undertaking Go/No-go, Loss/No-loss, and covert (aversive) face emotion recognition tasks during
functional magnetic resonance imaging (fMRI). Blood oxygenation level dependent responses were analyzed using
Statistical Parametric Mapping (SPM2). The tasks activated prefrontal and subcortical regions generally consistent
with literature with lateral orbitofrontal cortex (BA47) common to the three tasks. Citalopram pretreatment
enhanced the right BA47 responses to the No-go condition, but attenuated this response to aversive faces.
Attenuations were seen following citalopram in the medial orbitofrontal (BA11) responses to the No-go and No-loss
(i.e. relative reward compared with Loss) conditions. The right amygdala response to aversive faces was attenuated
by citalopram. These results support the involvement of serotonin in modulating basic processes involved in psychiatric
disorders. The technique of combining drug challenge with fMRI (pharmacoMRI) has promise for investigating human
psychiatric disorders and has the potential to be an add on to studies on depression to confirm brain activation
|
| |
|
|
For more information
on Facial Recognition and Pharmacological fMRI models or to discuss depression
studies contact Info@p1vital.com
| |
