Atypical antipsychotics: how do they work?

6 ~mpllcations for the development of new treatments lor schizophrema

symptoms in schizophrenia The simultaneous presence of decreased and increased dopamlne actwlty has important

Pathophysiology of schizophrenia: insights from neuroimaging Daniel R. W e i n b e r g e r Intramural Research Program, NIMH, NI1-L Bethesda, MD, USA Ke3' words Schlzophrema, MRI, PET, Prefrontal cortex, Hlppocampus

lng when patients are examaned during prefrontal type cognmve tasks. Recent data suggest, moreover, that hyperactivity of mesial temporal cortex may be a state independent functional characteristic In a study of discordant MZ twins, we have found that during prefrontal type cognitlon, prefrontal cortex is invariably hypofunctional and hlppocampal region is invariably hyperfunctional in affected as compared with unaffected twins Overall, the data suggest a developmental defect and functional disorganization of prefrontal-temporal-timbic connectivity

Neurolmagmg studies of schizophrenia have provided much of the foundation upon which current views of the pathophyslology of this disorder are based. Anatomical studies, most recently using MRI, have demonstrated subtle reductions m cortical volume, most consistently in structures of the llmblc temporal lobe In studies of discordant MZ twins, such subtle anatomical differences consistently differentmte affected from unaffected twm_ Functional imaging with PET and related methods have shown that hypoactivity of prefrontal cortex ~s a consistent find-

Fronto-limbic integration in schizophrenia: abnormal functional connectivity measured

with

PET

K.J.

Friston

The Neurosctences InStitute, New York, NY 10021, USA Key words Prefrontal; Temporal; PET, Connectivity, Fluency

Neurodevelopmental and cognmve models of schizophrenia have emphasized abnormal fronto-limbic interactions [1,2]. There is evidence for physiological abnormalities m prefrontal cortex [1,3] and medial temporal lobe [4], yet little is known about how these areas interact Recent advances in functional imaging now allow the functional connectivity between cortical areas to be assessed [5]. Functional connectivity is simply the correlation between remote neurophysiological events. These correlations define distributed systems called spatial modes To be part of mode a region must exhibit strong functional connections with the areas which conshtute that mode We present evidence that confn-ms the hypothes~s that

(1) m normal subjects, the dorsolateral prefrontal cortex (DLPFC) and temporal regaons are jointly implicated in a spatial mode engaged by a series of word generation tasks (designed to activate the DLPFC), and (u) the temporal regions are missing from the corresponding modes m schlzophremc subjects_ 1 2 3

Wemberger, D_R (1987) Arch Gen Psychlat, 44 660-669. Frith, C D and Done, D J_ (t989) Br J_ Psychaat, 155 437 1443 Llddle, PF, Fnston, K J., Frtth, C D et al (1992) Br J Psychiat, 160

4 5

Fnston, K J, Liddle, PF, Fnth, C D et al (1992) Brain, 115 367-382 Fnston, K J , F n t h , C.D,Llddle, P-F etal (1993) J Cereb BloodFlow Metab, 13 5-14

179-186

Atypical antipsychotics: how do they work? H e r b e r t Y. M e l t z e r Case WesternReserve Umverstty School of Me&cine, Cleveland, OH, USA Key words_ Clozapme, Serotonin, Dopamme, Atypical

Many antipsychotic drugs, in addition to clozapine, are considered to be atypical, e.g, thioridazine, remoxipnde,

melperone, when the criterion is the ability to produce less extrapyramidal symptoms (EPS) than standard neurolep-

7 tics It is unhkely that the low EPS profile of these diverse drugs is due to a single mechamsm The atypical profile of clozapine, by far the best stu&ed and most important of these agents, is no doubt partially dependent upon its llrmted ability to block strlatal D 2 DA receptors While remoxiprlde is a potent D2 receptor antagomst, low D2 occupancy cannot explain the clear advantages of clozaplne with regard to tardive dysklnesla and for treating positive and negative symptoms, improvement in cognitive function, or delayed onset of action, other features which may be considered part of atypicality. Additional

pharmacologic aspects of the mechanism of action of clozapine, m probable order of importance, include: (1) blockade of 5-HT2 and DI receptors; (2) blockade of D3, D4, al- and ct2-adrenerglc receptors, 5-HTlc, 5-HT3, 5HT6, and 5-HT 7 receptors_ Clozaplne also increases striatal glutamate effiux and DA effiux in the cortex and mesolimbic areas. On a more speculative basis, ~t is possible that clozaplne may prevent neurotoxlc processes in the brain and direct a structural reorganization of synaptic relationships The effect of clozapine to alter HPA axis function may be important to this process

Author Index Akll, H, 2 Benes, F M, 2 Blakely, R.D., 2

Kahn, R S., 5 Kleinman, J E, 4 Meltzer, H Y, 6

Charney, D S, 5 Claranello, R D , 3

Nemeroff, C.B, 4

Frlston, K J., 6

Tsuang, M T., 3

Goldman-Raklc, ES., 3

Weinberger, D.R, 6

Ralchle, M E., 4