How do antipsychotics and antidepressants really work? Is it just because they increase your hunger?
There appears to be a general consensus that antipsychotics increase appetite and subsequent weight gain. From Esen-Danaci et. al., 2008:
Weight gain is a major side effect of antipsychotic treatment which
contributes to morbidity and poor treatment compliance. Several of
the newer atypical antipsychotic agents have profound effects on
weight, the greatest increases occurring with clozapine and olanzapine
(Allison et al., 1999). Obesity has its inevitable consequences,
which are increasingly observed in patients receiving antipsychotic
drugs; such consequences may include the ‘metabolic syndrome’ of
hypertension, cardiovascular disease, dyslipidaemia and impaired
glucose tolerance, which may lead to type 2 diabetes (Henderson,
2002; Koponen et al., 2002).
It also appears that some antidepressants also lead to weight gain and increase probability of metabolic syndrome (Dodd and Berk, 2008). As for specific examples tricyclic antidepressants (TCA) (for review see Ruetsch et. al., 2005) are reported to cause an increase in weight. Mirtazapine, another antidepressant also leads to weight gain (Fava et. al., 2001). Selective serotonin reuptake inhibitors (SSRI) are a bit different, as they are reported to cause a transient drop in body weight (at least partially due to the drug induced nausea) followed by a gain in weight, at least in some cases (see Ruetsch) (though others will develop anorexia). The effect of long term SSRI on weight surprisingly has not been well studied - but a recent review (Demyttenaere and Jaspers 2008) conclude that long term use of SSRI leads to weight gain (though there are reported differences between specific SSRIs).
Therefore, it appears that many (but not all) antipsychotics and antidepressants increase weight gain, which suggest they increase appetite.
Yesterday, I posted on how dietary restriction, which obviously leads to feelings of hunger, also has antidepressant-like effects in animal models. When you do not eat a hormone called ghrelin increases which increases your appetite as a ‘motivator’ for you to eat. As I talked about yesterday, the researchers also found injections of ghrelin acted like an antidepressant.
I wondered then if maybe at least a partial mechanism behind how antidepressants work (and possibly antipsychotics) is via the increased appetite , and the likely increase in ghreli.
With a quick scan of pubmed I found these results:
A 2008 review (Jin et. al., 2008) examined papers from Jan 1999 to Jan 2007 and report that of the 8 papers that studied atypical antipsychotics effects on ghrelin levels; 2 showed decreased ghrelin levels, 3 showed no change, and 3 reported increase ghrelin levels. The authors point out that in all three long term studies (6+ months) researchers found an increase in ghrelin levels in those taking antipsychotics.
In a more recent paper, Esen-Danaci et. al., 2008 examined 5 different atypical antipsychotics (clozapine, olanzapine, risperidone, quetiapine, and amisulpride) taken for at least 1 year and found 4 out of the 5 resulted in higher ghrelin levels compared to control (the quetiapine group did not have increased ghrelin levels). Atypical antipsychotics are used to treat:
psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia. Some carry FDA approved indications for acute mania, bipolar mania, psychotic agitation, bipolar maintenance, and other indications.
Less research has been done on antidepressant effects on ghrelin. However, Pinar et. al., 2008 studied lean human subjects before and after 30 days of an antidepressant (maprotiline; a tetracyclic antidepressant) and found an increase in ghrelin after 30 days. However, SSRI in rats decrease ghrelin levels (Fujitsuka et. al., 2008). SSRIs are also linked with weight loss in rats due to acting as a 5HT2c receptor agonist (Halford et. al., 2007). But the human data from above suggest that long term use of SSRI tend to lead to weight gain - hence increased appetite?
Potential take home message:
There appears now to be several papers that suggest that many antipsychotics and at least some antidepressants increase ghrelin levels - at least in the long term (though SSRI still open to debate in humans). It is argued that for antidepressants to be effective they have to be used for a considerable time. Are the potential anti-depressive effects of antidepressants at least partly mediated by an increase in ghrelin? What about antipsychotics?
If this is true this might lead to some interesting questions and possible adjustments in our thinking. Do the patients that have the most increase in appetite, the most increase in ghrelin get the most benefits? Do the people the overeat the most taking antidepressants lose the positive effects by dampenning the ghrelin levels (eating in general decreases ghrelin level as the mirror image of not eating increases ghrelin levels)?
Can we increase antidepressants effect by being aware of gherlin levels?
As for SSRIs - I would like to see some long term human studies examining ghrelin levels.
This all might be well known in the anti-depression literature/community but I couldn’t find it spelled out for me. Maybe someone more knowledgeable in this field could comment.
At least some food for thought.
Update: I would like to thank the neurocritic for pointing some of my mistakes in this piece - which I have tried to correct in this updated version.
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