Zanos et al. reply

Clinical data have demonstrated rapid and sustained antidepressant effects of ketamine, a noncompetitive NMDAR (N-methyl-daspartate receptor) antagonist. Recently, Zanos et al.2 claimed that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) is essential for the antidepressant effects of ketamine in mice in an NMDAR-independent manner, although no alternative mechanism was proposed, beyond unspecific activation of AMPAR (α -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor). Here we report that (2R,6R)-HNK blocks synaptic NMDARs in a similar manner to its parent compound, and we show that the effects of (2R,6R)-HNK on intracellular signalling are coupled to NMDAR inhibition. These data demonstrate that (2R,6R)-HNK inhibits synaptic NMDARs and subsequently elicits the same signal transduction pathway previously associated with NMDAR inhibition by ketamine

McLean-Harvard International First-Episode Project:two-year stability of DSM-IV diagnoses in 500 first-episode psychotic disorder patients.

OBJECTIVE: Since stability of DSM-IV diagnoses of disorders with psychotic features requires validation, we evaluated psychotic patients followed systematically in the McLean-Harvard International First Episode Project. METHOD: We diagnosed 517 patients hospitalized in a first psychotic illness by SCID-based criteria at baseline and at 24 months to assess stability of specific DSM-IV diagnoses. RESULTS: Among 500 patients (96.7%) completing the study, diagnoses remained stable in 77.6%, ranking as follows: bipolar I disorder (96.5%) > schizophrenia (75.0%) > delusional disorder (72.7%) > major depressive disorder (MDD), severe, with psychotic features (70.1%) > brief psychotic disorder (61.1%) > psychotic disorder not otherwise specified (NOS) (51.5%) >> schizophreniform disorder (10.5%). Most changed diagnoses (22.4% of patients) were to schizoaffective disorder (53.6% of changes in 12.0% of subjects, from psychotic disorder NOS > schizophrenia > schizophreniform disorder = bipolar I disorder most recent episode mixed, severe, with psychotic features > MDD, severe, with psychotic features > delusional disorder > brief psychotic disorder > bipolar I disorder most recent episode manic, severe, with psychotic features). Second most changed diagnoses were to bipolar I disorder (25.9% of changes, 5.8% of subjects, from MDD, severe, with psychotic features > psychotic disorder NOS > brief psychotic disorder > schizophreniform disorder). Third most changed diagnoses were to schizophrenia (12.5% of changes, 2.8% of subjects, from schizophreniform disorder > psychotic disorder NOS > brief psychotic disorder = delusional disorder = MDD, severe, with psychotic features). These 3 categories accounted for 92.0% of changes. By logistic regression, diagnostic change was associated with nonaffective psychosis > auditory hallucinations > youth > male sex > gradual onset. CONCLUSIONS: Bipolar I disorder and schizophrenia were more stable diagnoses than delusional disorder or MDD, severe, with psychotic features, and much more than brief psychotic disorder, psychotic disorder NOS, or schizophreniform disorder. Diagnostic changes mainly involved emergence of affective symptoms and were predicted by several premorbid factors. The findings have implications for revisions of DSM and ICD