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She didn't even get anything that exotic; She got propofol and a little touch of fentanyl, something that we
use every day in millions of surgeries every year.

There seems to be this convergence between dream-like states, expectations/placebo effects, and
psychedelics. We don’t understand the neurobiology of this dream state. Humans aren’t supposed to be
in a prolonged dream state given that immobility makes us vulnerable.

Usually, when you have a nightmare, you have an autonomic escape. Your heart rate and your blood pres-
sure will rocket you out of dreams, into conscious awareness. That's something that modern anesthetics
are able to mitigate. Meanwhile, we're able to produce these longer states of dreaming and we really don't
know their full potential.

I think we'll see some interesting things when we start combining psychedelics with this stabilized kind of
quasi-sleep. This to me is so exciting.

The Role of Kappa Opioid Receptors (KORS) in Mediating

Transdiagnostic Symptoms: Will this Change the DSM as

We Know it?

A novel kappa opioid receptor antagonist is being studied targeting anhedonia rather than
the whole syndrome of depression. This is a new direction in psychiatry.

The Big Idea with KORs and Anticaprant:

• Antagonism of kappa opioid receptors (KOR), as exemplified by the novel KOR antagonist Aticaprant,

has downstream effects on symptoms of dopamine dysregulation such as anhedonia, stress-induced
failure to cope, attention deficits, and drug craving.
• KORs influence discrete transdiagnostic symptoms—aka symptoms shared by multiple DSM disor-
ders. The DSM is going to evolve towards categorizing illness based on symptoms that have a distinct

biological underpinning.
• KOR antagonism turns out to be another part of ketamine’s mechanism of action for depression.
Those of us who have worked with ketamine are not surprised by this as restoration of hedonic drive is

one of the first improvements we see in patients receiving ketamine.

How did this story unfold?

Aticaprant is a result of a new initiative at the NIMH called Fast Fail Trials or FAST.

FAST was developed to address the failure of current psychiatric treatments to adequately address symp-
toms and the growing costs and failure rate associated with central nervous system drug development that

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NORTHERN CALIFORNIA PSYCHIATRIC SOCIETY Page 16 January / February 2023