I hadn't seen that pooled results paper! Good to know that the pooled data still show a strong signal for improvement in negative symptoms, though effect size is the same.
Re: Metabolic side-effects. Depends on what you mean by long term. Significant weight gain (>7% of baseline body weight) with the more metabolically deleterious antidopaminergics like olanzapine can be seen on the order of weeks. There's at least one paper that has shown changes in insulin resistance and lipid abnormalities in healthy controls after just a single dose!
The mechanisms of weight gain in the antidopaminergics are still being elucidated, but there are at least 2 major ones that I am aware of. (1) Dopamine does some paracrine signaling in the pancreatic islets to regulate insulin release; (2) H1 antagonism increases appetite. Clearly there is more going on here - risperidone does both of those things but only seems to feature weight gain, not dyslipidemia or insulin resistance.
However, xanomeline doesn't do either of those things. My hunch is that if there's no significant weight gain after 5 weeks (doesn't seem like there is in any of the EMERGENT data), that's a good sign that we won't see more. Still, we need to see what the long-term data says.
I'd check out the Huhn et al. review from the Sept 2019 edition of The Lancet (https://linkinghub.elsevier.com/retrieve/pii/S0140673619311353) to see a good overview of the effect sizes of individual antipsychotics.
I hadn't seen that pooled results paper! Good to know that the pooled data still show a strong signal for improvement in negative symptoms, though effect size is the same.
Re: Metabolic side-effects. Depends on what you mean by long term. Significant weight gain (>7% of baseline body weight) with the more metabolically deleterious antidopaminergics like olanzapine can be seen on the order of weeks. There's at least one paper that has shown changes in insulin resistance and lipid abnormalities in healthy controls after just a single dose!
The mechanisms of weight gain in the antidopaminergics are still being elucidated, but there are at least 2 major ones that I am aware of. (1) Dopamine does some paracrine signaling in the pancreatic islets to regulate insulin release; (2) H1 antagonism increases appetite. Clearly there is more going on here - risperidone does both of those things but only seems to feature weight gain, not dyslipidemia or insulin resistance.
However, xanomeline doesn't do either of those things. My hunch is that if there's no significant weight gain after 5 weeks (doesn't seem like there is in any of the EMERGENT data), that's a good sign that we won't see more. Still, we need to see what the long-term data says.
Happy to help, discussions like these are what our work is all about, no? Keep up the good work!