Ketamine and neuroticism: a double-hit hypothesis of internalizing disorders

Abstract

Psychiatric disorders can often be viewed as extremes of personality traits. The primary action of drugs that ameliorate these disorders may, thus, be to alter the patient's position on a relevant trait dimension. Here, we suggest that interactions between such trait dimensions may also be important for disorder. Internalizing disorders show important differences in terms of range of activity and speed of response of medications. Established antidepressant and anxiolytic medications are slow in onset and have differing effects across different internalizing disorders. In contrast, low-dose ketamine is rapidly effective and improves symptom ratings in all internalizing disorders. To account for this, we propose a "double hit" model for internalizing disorders: generation (and maintenance) require two distinct forms of neural dysfunction to coincide. One hit, sensitive to ketamine, is disorder-general: dysfunction of a neural system linked to high levels of the personality trait of neuroticism. The other hit is disorder-specific: dysfunction of one of a set of disorder-specific neural modules, each with its own particular pattern of sensitivity to conventional drugs. Our hypothesis applies only to internalizing disorders. So, we predict that ketamine will be effective in simple phobia and (perhaps partially) in anorexia nervosa, but would make no such prediction about other disorders where neuroticism might also be important secondarily (e.g. attention deficit hyperactivity disorder and schizophrenia).

Right frontal anxiolytic-sensitive EEG ‘theta’ rhythm in the stop-signal task is a theory-based anxiety disorder biomarker

“…4 e). We also argue 43 that there are a range of anxiolytic-insensitive neurotic disorders where the “second hit” is, for example, high periaqueductal gray reactivity in those diagnosed with panic disorder 48 , 49 . Critically, with a neurotic background, ‘theta’ pathology could evoke panic attacks as a symptom, and panic pathology could elicit (via learning) otherwise normal ‘theta’ at an undesirably high level, or both could co-occur.…”

“…We emphasize that we do not think the process detected by our prospective biomarker is sufficient for the disorder specifically related to it; nor is it necessary for what DSM or ICD currently group together as classes of “anxiety” 15 disorder. We argue 43 that there is a general class of neurotic disorders 44 , where a “double hit” involving two distinct personality traits is necessary for the disorder to manifest: one, more specific, trait determines which type of neurotic disorder will occur; and a second, more general, trait is both a risk factor for, and a necessary factor underlying, neurotic disorders in general. In the case of the trait detected by our biomarker, we would expect both it (indexed by ‘theta’) and the general trait to be high; and if either of these is reduced—by an anxiolytic or ketamine 45 – 47 , respectively—then the disorder will be ameliorated (slowly or quickly, respectively).…”

Therapeutic Potentials of Ketamine and Esketamine in Obsessive–Compulsive Disorder (OCD), Substance Use Disorders (SUD) and Eating Disorders (ED): A Review of the Current Literature

“…These are conditions characterized by internal distress that include the DSM-5 [99] diagnoses of generalized anxiety disorder, social anxiety disorder, MDD, panic disorder and OCD, which are all thought to share the common trait of neuroticism. Neuroticism is defined as a genetically inherited trait that reflects individual differences in response to subjective distress and negative affectivity, but it is not itself considered to be a form of psychiatric disorder [100]. Nevertheless, all "internalizing disorders" involve dysfunctions in different neural systems and are differentially impacted by traumatic or chronically stressful events [101].…”

Personality neuroscience and psychopathology: should we start with biology and look for neural-level factors?

“…Some coordinated, evolutionarily old, responses (such as the stress response) can involve the concerted activity of several modulators (cortisol/corticosterone, serotonin, noradrenaline); others may involve the summated separate actions of more than one such modulator (with panic-proneness likely controlled by both more general serotonergic "stability" and a CCK-sensitive panic-specific trait) and specific disorders may involve the combination of high levels of more than one trait. For example, the general class of neurotic disorders appears to require an extreme of both neuroticism and an extreme of trait panic or trait anxiety, or trait obsession (McNaughton & Glue, 2020). Other traits (like murmuration) may be emergent.…”