Barcelona snapshots

Prof. Herbert Y. Meltzer

Herbert Y. Meltzer psychiatrist Controversias Psiquiatry Barcelona
Northwestern University, USA
Talk The Neurobiology of Treatment Resistance: Beyond Dopamine and Persistent Psychosis
Date Friday, April 26th, 2019
Time 11:00 to 11:45
Round Table Treatment-resistance in schizophrenia


Herbert Y Meltzer, MD, is Professor of Psychiatry and Behavioral Sciences and Professor of Pharmacology and Physiology at the Northwestern University Feinberg School of Medicine, Chicago, Il He has been President of the American College of Neuropsychopharmacology (ACNP) and the Collegium International Neuro-psychopharmacologicum (CINP). He has published >950 peer reviewed publications and 150 book chapters, relating to schizophrenia, mood disorders and suicide, addressing both clinical and basic neuroscience aspects (Hirsch Index 116). His research emphasizes translational neuropsychopharmacoloty. Dr Meltzer led the research for approval of clozapine for treatment resistant schizophrenia and suicide ,and the use of atypical antipsychotic drugs to treat the cognitive impairment of schizophrenia. More recently, he led the development of the first non-dopamine antagonist-based antipsychotic drug, pimavanserin, a selective 5-HT2A antagonist, now approved for treatment of Parkinson’s psychosis.

Dr. Meltzer is the recipient of the Research Prize of the American Psychiatric Association (2005), the Lifetime Achievement Award of the Schizophrenia International Research Society(2016), the Pioneer Award of the International College of Neuropsychopharmacology (2016) and numerous other awards.

Current research interests include: 1) the discovery and elucidation of the mechanism of action of novel pharmacologic treatments for schizophrenia and related psychiatric disorders, neurodegenerative diseases, and aging, as well as rapidly acting antidepressants and anti-suicide drugs (e.g. rapastinel); 2) pharmacogenetic tests to predict response to antipsychotic drugs; and 3 animal models of components of the psychotic spectrum disorders.


Schizophrenia, bipolar disorder, and major depression with psychotic symptoms are often classified as separate diseases but are more accurately thought of as syndromes within the Psychotic Spectrum Disorder(PSD). A very large number of risk genes for these syndromes are shared and that copy number variations and chromosomal abnormalities may produce all of these syndromes. Psychosis, cognitive impairment, mood disturbances, reward and motor behaviors and suicidality overlap, with differences in severity and timing within and between patients. Atypical antipsychotic drugs (APDs) are often effective to treat these symptoms but response ranges from complete control to total resistance. Typical APDs, e.g. haloperidol and perphenazine, are effective to treat psychosis, and are ineffective in some patients whose psychosis responds to clozapine or other atypical APDs.

The discovery that the first generation of atypical APDs (clozapine, melperone) shared in common more potent 5-HT2A than dopamine (DA) D2 receptor blockade (Meltzer et al. 1989), but also a variety of other direct and indirect neurotransmitter and neurotrophic effects, led to the development of the remarkable group of compounds, now called atypical APDs. These have been shown in controlled trials to be effective in schizophrenia, bipolar disorder and psychotic depression for phenotypic features but only in some patients.

We will illustrate this view of the disorders as a spectrum and treatment response as a continuum with a patient, unique to our knowledge, whose manifested bipolar disorder for 2 years beginning at age 18, followed by a 20 year history of recurrent psychotic depressions, which were replaced by schizophrenia psychopathology that was initially responsive to atypical APDs but then became treatment resistant for a period of 4-5 years, followed by complete remission and functional recovery(Meltzer,2018).

We will present evidence that the response to atypicals APDs is based upon their ability to modulate synaptic plasticity. This is a product of their ability to enhance the release of multiple neurotransmitters and neurotrophic factors, including, but not limited to DA, ACh, NE, 5-HT, trace amines, BDNF, and neuregulin. This enables them to affect the expression and function of a variety of proteins that are important for the formation and function of dendrites and the receptors that are needed for signal transduction that permit integrated action of principal neurons and interneurons. Treatment response and resistance is the net result of the ability of these processes to restore synaptic function, enabling integrated communication within and between neural circuits. Treatment resistance occurs when such integrated neuronal activity is not possible which may be the result of inherited or acquired (epigenetic) abnormalities.


Meltzer HY, Matsubara S, Lee JC (1989). Classification of typical and atypical antipsychotic drugs on the basis of dopamine D 1, D 2 and serotonin2 pKi values. Journal of Pharmacology and Experimental Therapeutics 251:238 46, 1989. PMID: 2571717

Li J., Yoshikawa A., Brennan MD, Ramsey TL, Meltzer HY (2018). Genetic predictors of anitipsychotic response to lurasidone identified in a genome wide association study and by schizophrenia risk genes. Schizophrenia Research. 2018 Feb;192:194-204. doi: 10.1016/j.schres.2017.04.009. Epub 2017 Apr 19. PMID: 28431800

Li J, Loebel A, Meltzer HY (2018). Identifying the genetic risk factors for treatment response to lurasidone by Genome-wide Association Study: a meta-analysis of samples from three independent clinical trials. Schizophrenia Research. 2018 May 2. pii: S0920-9964(18)30195-6. doi: 10.1016/j.schres.2018.04.006. PMID: 29730043

Li J, Meltzer HY (2014). A genetic locus in 7p12.2 associated with treatment resistant schizophrenia. Schizophr Res. 2014 Nov; 159(2-3): 333-9. PMID: 25223841