Molecular (2002) 7, 247–253  2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp MECHANISMS OF DRUG ACTION The substituted and their clinical potential on and on the negative symptoms of L Pani1 and GL Gessa2

1Center for Neuropharmacology, National Research Council, Neuroscienze Scarl, Cagliari, Italy; 2‘BB Brodie’ Department of Neuroscience, University of Cagliari, Cagliari, Italy

In this paper the historical and scientific background that led to the use of substituted benzamides in two apparently unrelated clinical conditions namely dysthymic disorder and schizophrenia will be reviewed, in order to understand if a common mechanism of action may support this dual therapeutic indication. The action of substi- tuted benzamides such as , has been proposed, since the late 1970s, by several authors and extensively explored in preclinical experiments by our group. In Italy the first marketing authorization obtained for the new substituted , was with the sole indication of dysthymia and therefore a solid clinical experience exists in the use of substituted benzamides in mild forms of , with more than 1 000 000 patients being treated in the last 7 years. The proposed mechanism of action of substituted benzamides implies a selective modulation of the dopaminergic system in the mesocorticolimbic area, important for cognitive processing of internal and external cues, related to survival. The selec- tive antagonism of D2–D3 receptors has been evoked to explain, in small to moder- ate doses (ie 50–100 mg day−1), the antidepressant effect and, in moderate to medium doses (100–400 mg day−1), the reported efficacy on negative symptoms of schizophrenia. Thus, sub- stituted benzamides could represent the first class of atypical successfully employed for both depressive states and schizophrenia. Interestingly, recent evidence in the literature suggests that depressive episodes belonging to the bipolar spectrum are among ‘alternative indications’ of other atypical antipsychotics such as and . Molecular Psychiatry (2002) 7, 247–253. DOI: 10.1038/sj/mp/4001040 Keywords: antidepressant; affective disorders; depression; dopamine; limbic system

Introduction on the market. If instead three additional criteria, with less consensus in the literature—such as a decreased, Between 1954 and 1975, about forty or non-existent, capacity to induce hyperprolactine- drugs were introduced throughout the world. There- mia,3 weight gain4,5 and better effectiveness in some after, there was a hiatus in the development of antipsy- patients previously regarded as treatment-refractory6— chotics until the re-introduction of in the would be stringently added as essential features in the United States in 1990 reopening the era of ‘atypical’ atypical profile of an antipsychotic, then most of the antipsychotics.1 Among the various criteria used to ‘new’ antipsychotics could not be considered atypicals. label an antipsychotic as atypical a consensus has In the search for new atypicals, the attempt to match emerged among clinicians that led to the definition of the unique therapeutic profile of clozapine has been at least two fundamental parameters: (1) decreased (or rooted in three notions which have been utilized to non-existent) capacity to cause acute extrapyramidal explain its distinction with respect to classical motor side effects (acute EPS) and tardive neuroleptics: (1) dose-response separation between (TD); (2) increased therapeutic efficacy reflected by particular pharmacological functions; (2) anatomic improvement in positive, negative, or cognitive symp- specificity of particular pharmacological activities; toms.2 (3) receptor interactions and pharma- If only these two criteria were to be applied, then codynamics.2 atypicals were already present since the early 1970s, As a consequence of this conceptual framework when clozapine and most substituted benzamides were atypicals were generated by two ‘schools of ’: the first one leading to designing drugs similar to cloza- pine (the low antidopaminergic approach) without the Correspondence: L Pani, Center for Neuropharmacology, CNR, via Porcell, 4, 09124-I Cagliari, Italy. E-mail: panilȰunica.it danger of the hematological side effects; the other aim- Received 24 May 2001; revised 20 August 2001; accepted 20 ing at synthesizing selective dopamine (DA) receptor October 2001 antagonists based on the findings on benzamides Substituted benzamides in depressive states L Pani and GL Gessa 248 which had shown a peculiar property, ie the large gap ‘other indications’ of antipsychotics were already pro- between the dose needed to antagonize the central posed in the early 1980s.26,27 effect of or and that neces- In order to understand whether the proposed selec- sary to produce in rodents (the selective DA tive mechanism of action on the dopaminergic system receptors approach).7 may underlay a dual therapeutic indication and in the It must be stressed that these conceptual bases are attempt to draw the scientific community attention to not mutually exclusive and that, in addition, areas of the possibility that a different daily dosage of the same common functions between different atypical as well compound might treat distant psychopathological con- as first generation antipsychotics have been considered ditions, we will review the historical and scientific instrumental to our identification of shared pathophy- background that led to the rationale behind the use of siological dimensions of schizophrenia, including substituted benzamides in two otherwise apparently negative symptoms, and depression.8 For instance, dif- unrelated clinical conditions, namely dysthymic dis- ferent depressive states, irrespective of their diagnostic order and schizophrenia. categorization, share in common the incapacity to anticipate, seek and consume ‘pleasures’ (ie conditions Dopamine, depression and schizophrenia that produce reward) and a decreased cognitive ability 28 to properly perform in everyday life, suggesting a poss- Almost fifty years of research (reviewed in Carlsson ) ible common neurobiological basis between ‘emotions’ have implicated DA both in depressive states and in and . schizophrenia. In particular, numerous experimental Accordingly to the above model, strong experimental evidence converges to suggest the crucial role of meso- evidence has shown that the functions that are con- corticolimbic DA in the neurobiological response to 29,30 31,32 trolled by the mesocorticolimbic DA system are rewarding stimuli, and to sensory-specific cues, 33 impaired in depressive disorders of a different nature, considered to be linked to incentive and/or 34 and whenever symptoms of depression can be to associative learning, which has been speculated to 35 mimicked in experimental animals they appear to be be impaired in depressive states of different nature. sustained by a deficit in mesocorticolimbic DA The finding that produced depression by transmission. Thus, a deficit in mesocorticolimbic DA reducing the brain content of biogenic amines allowed transmission may represent the common neurobiolog- the original formulation of the hypotheses about the role of monoamines, and particularly DA, in ical substrate of the core symptomatology in different regulation and in the action of antidepressant drugs, depressive conditions independently of their nosologi- which has been recently reviewed elsewhere.36,37. cal classification, including dysthymic disorder, major Abnormalities in DA neurotransmission have also depressive disorder, drug-induced depression and, long been thought to play a role in the pathophysiology possibly, negative symptoms of schizophrenia.9 of schizophrenia,38,39 although more recently the nat- The dopaminergic antidepressant action of com- ure of these abnormalities has been the subject of sub- pounds belonging to the substituted benzamides fam- stantial debate. Recently PET data have shown that the ily—such as sulpiride—has been proposed by several 40–42 43 10–12 synthesis, and the basal as well as the amphetam- groups since the late 1970s, and extensively 44–46 13–15 ine-induced release of DA is increased in explored in Italy by our group. It is not surprising drug-naive schizophrenic patients, compared with therefore that, in this country, the first marketing age-matched controls. authorization obtained for the new substituted benza- Recent formulations of the DA hypothesis of schizo- mide amisulpride, was with the sole indication of dys- phrenia posit that the psychotic symptoms of this dis- thymia. In Italy, there is solid clinical experience in order reflect a hyperdopaminergic state in subcortical the use of amisulpride in mild forms of depression, structures, whereas negative/depressive symptoms and with more than 1 000 000 patients being treated to the cognitive deficits have been attributed to a hypodo- 16 date. The proposed mechanism of action of substi- paminergic state in certain cortical association regions, tuted benzamides implies a selective modulation of the such as the prefrontal (PFC) and entorhinal cortices.47– dopaminergic system in the mesocorticolimbic area, 49 Pharmacological evidence sustains the first part of which has been called forth to explain the antidepress- this hypothesis: compounds that increase brain DA lev- ive effect,17,18 in small to moderate doses, including in els precipitate or exacerbate positive symptoms such as patients suffering from endogenous depression,11,19 or and and secondly, all hitherto autism20 and, in moderate to medium doses, a reported discovered antipsychotic drugs have been found to efficacy on negative symptoms of schizophrenia,21–23 antagonize central DA neurotransmission.50,51. This with relatively few extrapyramidal side effects.24 last point is difficult to reconcile with the fact that the Thus, substituted benzamides have been the first negative symptoms of schizophrenia are instead wors- class of atypical antipsychotics successfully employed ened by a decreased DA activity in the PFC.52,53 This for both schizophrenia and depression. Interestingly, apparent contradiction between high or low DA there is a growing evidence in the literature to suggest activity has been addressed by recent evidence from that depressive episodes belonging to the bipolar spec- model systems suggesting that reduced DA modulation trum are among ‘alternative indications’ of other atypi- of neuronal activity in the PFC can contribute to cal antipsychotics.25 It must said that some of these excessive DA activity in the subcortical areas.54

Molecular Psychiatry Substituted benzamides in depressive states L Pani and GL Gessa 249 Accordingly, increasing the DA output in the PFC classic or new antidepressants76 and by the substituted would have the dual therapeutic action of improving benzamides amisulpride,77 and sulpiride.78 the negative symptomatology and, consequently, the In the mild -induced model, postsynaptic DA positive one, by decreasing mesolimbic DA activity. receptors are hyposensitive while DA release is not Again, support for this hypothesis has come from the reduced, while in the psychostimulant-withdrawal clinical efficacy of the clozapine model there is an inhibition of DA output associated which, despite a lower D2 receptor occupancy in brain with supersensitivity of postsynaptic DA receptors. (that is, 45–50%),55 has remarkable therapeutic actions Thus, experimental data would suggest that the sole on both the positive and the negative symptoms of impairment of dopaminergic transmission could not be schizophrenia,56 and, in contrast to classical neurolep- regarded as essential for producing a depressive status tics, induces a marked increase in the DA output of the in the animal. The presence of hyper or hyposensitivity PFC.57,58 Clozapine’s superior efficacy is thought to be of postsynaptic DA receptors might explain the pres- based on its ability to influence the function of a broad ence or absence of psychotic symptoms, such as spectrum of neurotransmitter systems; in addition to delusions and agitation, in different depressive dis- its antagonism on DA receptors, clozapine is a potent orders (ie mixed states) or in the recurrences of schizo- antagonist of noradrenergic, serotonergic, muscarinic phrenic episodes. The therapeutic implication of such and histaminic binding sites.59 differences is that some episodes with psychotic fea- A different approach is that provided by substituted tures may be worsened by antidepressant treatments benzamides, starting from sulpiride, (available for that increase the monoamine concentration rather than clinical use since 196760) to the more recent amisulp- selectively modulate the dopaminergic tone in the ride,61 which share the ability to putatively block a dif- mesocorticolimbic system. ferent subclass of dopaminergic receptors. Owing to Interestingly, the strategy of dopaminergic stabiliz- this differential action, the clinical use of substituted ation has been recently proposed as a promising novel benzamides60 ranges from that of major neuroleptics, therapeutic approach in schizophrenia,79 by employing as in the case of and , to a tymolep- a series of compounds capable of modulating the dopa- tic-like, antidepressant and non sedative action, as in minergic system, without inducing the hypodopami- the case of sulpiride62 and amisulpride,63,64 albeit at nergia so common for most antipsychotics available to much lower dose.65 In addition, these drugs increase date. Some of these new drugs, belonging to the dopa- brain DA synthesis66 and turnover in DA terminal areas mine D2 receptor family partial agonists are now as demonstrated by an increased concentration of undergoing clinical trials.80 homovanillic acid in the brain of rodents67 and Others, such as phenyl-piperidines and benzamides, humans.68 Sulpiride is the oldest member of the are pure antagonists acting on the same D2 family of substituted benzamides class while amisulpride is the receptors, and thought to readjust elevated dopamine clinically most established. Their detailed levels without producing hypodopaminergia. The rea- pharmacodynamics are reported elsewhere.69,70 son for this aberrant pharmacological profile seems to and raclopride are two other recently be that they act on subpopulations of dopamine recep- described members of this class. They are also selective tors in a manner different from that of the currently D2 receptor blockers with preferential action in meso- used drugs.79,80 They either exert a strong action on limbic areas71 and their clinical efficacy has been dopaminergic autoreceptors and/or they have a weaker evaluated in several studies72–75 in which they showed effect postsynaptically, and/or they seem unable to an antipsychotic efficacy comparable to that of tra- reach a subpopulation of postsynaptic dopamine ditional neuroleptics, demonstrating that the selective receptors.81,82 dopaminergic approach has consistently produced The clinical significance of modulating, rather than compounds that are currently employed in the clinical simply decreasing or increasing DA transmission in the treatment of schizophrenia. PFC, stems from the fact that cognitive symptoms have been associated with the finding that DA levels in the PFC should be maintained in a precise range in order Modulation of the dopaminergic system: a to avoid functional impairment (see below). This has common therapeutic target for both depression been shown in numerous other than and schizophrenia? depression83 or schizophrenia;84 including Hunt- Several findings suggest that the reduction of DA trans- ington’s,85 drug addiction,86 and Parkinson’s87 as well mission might be produced via different mechanisms. as in normal aging.88 A variety of experimental and Long-term exposure of to mild stress causes a neuropsychological studies suggest a direct association decreased sensitivity to reward, which has been sug- between ‘unmodulated’ dopamine transmission in the gested as being homologous to , a specific PFC and cognitive deficits.89–91 trait of both depression and negative symptoms of schizophrenia. This behavioral effect in rats is associa- Should atypical antipsychotics be able to ‘modulate’ rather than impair PFC dopaminergic ted with a decreased responsiveness of D2/D3 DA receptors in the nucleus accumbens. Both the transmission? behavioral response and the decreased sensitivity of Beyond ’neuronal and dopaminergic’ dopamine DA receptors are reversed by chronic treatment with We have recently shown that the dopaminergic output

Molecular Psychiatry Substituted benzamides in depressive states L Pani and GL Gessa 250 in the PFC could be an expression of the activity of localized on non-dopaminergic and/or non-neuronal noradrenergic neurons as well.92 Atypical antipsy- (glia) cells. chotics by blocking DA autoreceptors localized on nor- adrenergic neurons would increase DA and NE output The role of dopamine D1 receptors not only from DA neurons but from noradrenergic neu- To complicate further the understanding of these cir- rons where these two monoamines may act as cotrans- cuits, one should bear in mind that when the PFC dis- mitters. In the same area approximately 35% of the tribution of DA receptors is studied, then the D1 family total D2 ligand binding activity is known to be associa- of dopamine receptors is at least 20-fold more abun- ted with isolated from rodents (mice and dant than the D2 family of receptors in this area.99,100 rats) and primates (monkeys and humans), while astro- The functional effect of dopaminergic neurotransmis- cytes isolated from D2 receptor knock-out mice failed sion in cortical circuits is not yet fully understood, but to show any D2-ligand binding.93 The functional nature the role of the DA D1 receptor has received a great deal of these receptors is sustained—directly—by the fact of attention, thanks to the seminal work of the group that a 25% increase in intracellular Ca2+ is induced led by Patricia Goldman-Rakic. These authors have after the local application of the D2-receptor-specific shown that the tuning of PFC neurons engaged in cog- agonist , an effect reversibly blocked by the nitive tasks is enhanced at moderate levels of D1 occu- substituted benzamide raclopride; and—indirectly—by pancy and reduced at both lower and higher levels of the observation that chronic treatment with D2-antag- occupancy. These findings may be relevant to both nor- onist drugs tend to alter the density of glial cells in the mal functioning and clinical conditions. It is of interest PFC of rhesus monkey,94 suggesting the existence of a that a recent PET study has revealed that the D1 recep- constant dopaminergic tone at the level of the PFC tor is decreased in the PFC of both medicated and non- glial network. medicated schizophrenic patients. In addition, the Since the electron microscopic analysis showed that density of D1 receptors was positively correlated with D2 receptors in the astrocytes make close anatomical performance of the patients on the Wisconsin Card 101 association with interneurons in the cerebral cortex, Sorting Task. Normal aging also brings with it a this suggests not only that this association might pro- decline in dopamine levels and D1 receptor func- tion102,103 and in working .104 Given the vulner- vide a substrate for the functional interaction between 105 the two cell types, but it may also imply that some of ability of cognitive functions to DA dysfunction, it would not be surprising if a common pathophysiolog- the differences between typical and atypical neurolep- ical process would be responsible both for cognitive tic drugs with respect to relief of clinical symptoms or processes in normal individuals, in schizophrenic and production of side-effects might account for thera- in depressed individuals with prominent cognitive peutic actions at glial targets. deficits.106 The exact nature of these receptors, whether belong- It appears therefore important that, in the action of ing to the D2Long (D2L) or the D2Short (D2S) iso- an antipsychotic (and perhaps of an antidepressant), a forms,95 must be ascertained, since they can represent selective blockade of DA D2 family receptors is an important pharmacological target for the action of preferred over an indiscriminate D1/D2 receptors selective dopaminergic atypical antipsychotics of the blockade. An antagonism at the level of the DA D2 benzamides class, as has been proposed for remoxi- 96 autoreceptor in the PFC, by increasing the DA output pride. If these recent data are confirmed, then the and DA action on D1 receptors, could ameliorate the proposed selective affinity of benzamides such as cognitive/negative symptomatology. sulpiride, remoxipride, raclopride and amisulpride97 for this subtype of DA receptor should be evaluated in order to better characterize their atypical profiles. The Conclusions heuristic value in the discovery of different isoforms Symptoms of both schizophrenia and depression and different cellular localization of the D2 receptor involve a reduction or absence of normal , is supported by reports which show that antipsychotic emotions, and behavior. Negative symptoms of schizo- drugs which elicit Parkinsonism (trifluperazine, chlor- phrenia, such as flatten affect, , or (A5 , raclopride, , fluphenazine) bind criteria),107 have significant overlaps with the clinical more tightly than dopamine to D2, while those antipsy- presentation of depressive disorders such as dysthy- chotic drugs which elicit little or no Parkinsonism mia. In dysthymia, negative symptomatology will be (, , clozapine, remoxipride, amis- present with variable levels of hedonic impairment, as ulpride, olanzapine, ) bind more loosely than in the melancholic type (eg finding no pleasure in dopamine to D2 receptors,98 irrespective of their doing any or almost any activities); cognitive impair- chemical structure (ie raclopride and amisulpride are ment (eg finding it difficult to concentrate and make both benzamides) and, perhaps more importantly, decisions); or lack of drive and will (eg demonstrating independently from the absolute levels of dopamine low levels of energy or ). In all cases, these types D2 receptors occupancy. The question arises whether of symptoms would produce clinically significant dis- the cataleptic propensity of atypical antipsychotics tress or impairment in work, social, or other areas of might be ascribed to their preferential affinity for one important functioning. The literature indicates that or the other of the DA D2 isoforms and/or for the D2 emotional-cognitive symptoms are much more charac-

Molecular Psychiatry Substituted benzamides in depressive states L Pani and GL Gessa 251 teristic of dysthymia than the vegetative and psycho- References motor symptoms of major depression, and recently two multicenter collaborative trials found that dysthymic 1 Shen WW. A history of antipsychotic drug development. Compr disorder appears to primarily involve psychologic Psychiatry 1999; 40:407–414. 2 Kinon BJ, Lieberman JA. Mechanisms of action of atypical anti- symptoms that seem to cluster into affective vs psychotic drugs: a critical analysis. Psychopharmacol (Berl) 1996; 108 cognitive deficits. Dysthymia proper, dominated by 124:2–34. negative affectivity, might be distinguishable from a 3 Petty RG. Prolactin and antipsychotic : mechanism of ‘neurasthenic’ subform dominated by low energy or action. Schizophr Res 1999; 35 Suppl: S67–S73. ‘deficit’ symptoms at mental and physical levels.109 On 4 Wetterling T. Weight gain from atypical neuroleptics—an underreported ? Fortschr Neurol Psychiatr 2000; 68: the other hand, anhedonic symptoms in schizophrenia 546–556. belong to the associated features of the disorder and, 5 Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, along with classical negative symptoms, are difficult to Infante MC et al. Antipsychotic-induced weight gain: a compre- distinguish from the alogia, blunted affect or avolition hensive research synthesis. Am J Psychiatry 1999; 156: 1686– of a dysthymic individual. 1696. 6 Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical anti- Since the monoamine hypothesis of depression pre- psychotics in the treatment of schizophrenia: systematic overview dicted an impairment in central func- and meta-regression analysis. BMJ 2000; 321: 1371–1376. tion, such deficiencies were thought to be reflected in 7 Hogberg T. The development of dopamine D2-receptor selective the absolute concentrations of monoamines. Until now, antagonists. Drug Des Discov 1993; 9:333–350. 8 Siris SG. Depression in schizophrenia: perspective in the era of measurement of the concentrations of the neuro- ‘atypical’ antipsychotic agents. Am J Psychiatry 2000; 157: transmitters and their metabolites in cerebrospinal 1379–1389. fluid, urine, and plasma of patients with depression 9 Gessa GL, Serra G (eds). Dopamine and Mental Depression. Perga- has yielded equivocal results regarding the possibility mon Press: Oxford. Adv in the Biosciences vol 77, 1990. of altered metabolism of these and 10 Muller RB. Therapy of various forms of senile depressions with sulpirid (Dogmatil). Z Allgemeinmed 1975; 51: 1546–1548. the development of sensitive markers of endogenous 11 Niskanen P, Tamminen T, Viukari M. Sulpiride vs 110 depression. However, very recently, using catheters in the treatment of depression. Curr Ther Res Clin Exp 1975; 17: placed in an internal jugular vein, the release of brain 281–284. monoamine neurotransmitters was estimated, at rest 12 Pelc I. Sulpiride and psychic decompensation. Encephale 1976; and following intravenous desipramine hydrochloride, 2:349–361. 13 Serra G, Argiolas A, Klimek V, Fadda F, Gessa GL. Chronic treat- in healthy volunteers and in patients with unipolar ment with prevents the inhibitory effect of small depressive illness refractory to . Surpris- doses of apomorphine on dopamine synthesis and locomotor ingly, while both the reduction in NE turnover and the activity. Life Sci 1979; 25:415–424. defect in cerebral metabolism were normalized follow- 14 Mereu G, Casu M, Gessa GL. (-)-Sulpiride activates the firing rate ing pharmacological blockade of the NE transporter and hydroxylase activity of dopaminergic neurons in unanesthetized rats. Brain Res 1983; 264:105–110. with desipramine, it was the brain’s turnover of DA 15 Serra G, Forgione A, D’Aquila PS, Collu M, Fratta W, Gessa GL. that bore a significant relation to the patients’ clinical Possible mechanism of antidepressant effect of L-sulpiride. Clin status.111 Neuropharmacol 1990; 13 Suppl 1: S76–S83. We have here argued that the proposed, albeit 16 Paizzis G, Italian Medical Dept. Sanofi–Synthe´labo. Data on file. debated,112 selective mechanism of action of the 17 Tsukamoto T, Asakura M, Tsuneizumi T, Satoh Y, Shinozuka T, Hasegawa K. Therapeutic effects and side effects in patients with atypical antipsychotics belonging to the substituted major depression treated with sulpiride once a day. Prog Neuro- benzamides class might sustain the possibility that a psychopharmacol Biol Psychiatr 1994; 18:615–618. different daily dosage of the same compound might 18 Smeraldi E. Amisulpride versus fluoxetine in patients with dys- treat distant psychopathological conditions such as thymia or major depression in partial remission: a double-blind, dysthymia and schizophrenia comparative study. J Affect Disord 1998; 48:47–56. 19 Benkert O, Holsboer F, Effect of sulpiride on endovenous A better understanding of how the DA system may be depression. Acta Psychiatr Scand 1984; 69:42S–48S. affected by external or internal stimuli—which usually 20 Elizur A, Davison S. The evaluation of the anti-autistic activity of precipitate affective or psychotic episodes—or by sulpiride. Curr Ther Res 1975; 18:578–584. drugs employed to treat such episodes, may offer not 21 Boyer P. Efficacy of low doses of atypical neuroleptics only a simplification of the nosological heterogeneity (benzamides) in defect states. Ann Med Psychol (Paris) 1986; 144: 593–599. of the different depressive states, but would also offer 22 Berner P, Kufferle B, Friedmann A, Grunberger J, Saletu B. Treat- a reasonable explanation for why certain second gener- ment of negative symptoms in schizophrenia with neuroleptics. ation antipsychotics may be successfully employed in Encephale 1989; 15: 457–463. both the depressive symptoms and signs which present 23 Danion JM, Rein W, Fleurot O. Improvement of schizophrenic themselves in the context of a depressive or a schizo- patients with primary negative symptoms treated with amisulp- ride. Amisulpride Study Group. Am J Psychiatry 1999; 156: phrenic cluster of mental disorders. 610–616. 24 Lavilli C, Margarit J. The effect of sulpiride on the . Path Biol 1968; 16:11–14. 25 Ghaemi SN, Cherry EL, Katzow JA, Goodwin FK. Does olanzapine Acknowledgments have antidepressant properties? A retrospective preliminary study. Bipolar Disord 2000; 2:196–199. 26 Robertson MM, Trimble MR. Neuroleptics as antidepressants. The AA are grateful to the English language proof-read- Neuropharmacology 1981; 20: 1335–1336. ing skills of David J Webb. 27 Nelson JC. The use of antipsychotic drugs in the treatment of

Molecular Psychiatry Substituted benzamides in depressive states L Pani and GL Gessa 252 depression. In: Zohar J, Belmaker RH (eds). Treating Resistant lation of dopamine system responsivity: a hypothesis for the etiol- Depression. PMA Corp: New York, 1987, pp 131–146. ogy of schizophrenia. Neuroscience 1991; 41:1–24. 28 Carlsson A. Thirty years of dopamine research. Adv Neurol 1993; 48 Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizo- 60:1–10. phrenia: a review and reconceptualization. Am J Psychiatry 1991; 29 Fibiger HC, Phillips AG. Role of catecholamine transmitters in 148:1474–1486. reward systems: implications for the neurobiology of affect. In 49 Goldstein M, Deutch AY. Dopaminergic mechanisms in the patho- Oreland E. (ed). Brain Reward Systems and . New York genesis of schizophrenia. FASEB J 1992; 6: 2413–2421. Press: New York, 1987, pp 61–74. 50 Carlsson A. The current status of the dopamine hypothesis of 30 Wise RA. The brain and reward. In: Liebman J, Cooper SJ. (eds). schizophrenia. Neuropsychopharmacology 1988; 1: 179–186. The Neuropharmacological Basis of Reward. Oxford University 51 Carlsson A. The dopamine theory revisited. In: Hirsch SR, Wein- Press: Oxford, 1989. berger DR (eds). Schizophrenia. Blackwell Science: Oxford, 1995, 31 Blackburn JR, Pfaus JG, Phillips AG. Dopamine functions in pp 379–400. appetitive and defensive behaviours. Prog Neurobiol 1992; 39: 52 Deutch AY. The regulation of subcortical dopamine systems by 247–279. the : interactions of central dopamine systems 32 Ahn S, Phillips AG. Dopaminergic correlates of sensory-specific and the pathogenesis of schizophrenia. J Neural Transm Suppl satiety in the medial prefrontal cortex and nucleus accumbens of 1992; 36:61–89. the rat. J Neurosci 1999; 19: RC29. 53 Fink-Jensen A. Novel pharmacological approaches to the treat- 33 Berridge KC, Robinson TE. What is the role of dopamine in ment of schizophrenia. Dan Med Bull 2000; 47: 151–167. reward: hedonic impact, reward learning, or incentive salience? 54 Saunders RC, Kolachana BS, Weinberger DR. Local pharmacologi- Brain Res Rev 1998; 28: 309–369. cal manipulation of extracellular dopamine levels in the dorsolat- 34 Bassareo V, Di Chiara G. Differential influence of associative and eral prefrontal cortex and in the rhesus monkey: nonassociative learning mechanisms on the responsiveness of pre- an in vivo microdialysis study. Exp Brain Res 1994; 98:44–52. frontal and accumbal dopamine transmission to food stimuli in 55 Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall rats fed ad libitum. J Neurosci 1997; 17:851–861. G. Positron emission tomographic analysis of central D1 and D2 35 Di Chiara G, Loddo P, Tanda G. Reciprocal changes in prefrontal occupancy in patients treated with classical and limbic dopamine responsiveness to aversive and rewarding neuroleptics and clozapine. Relation to extrapyramidal side stimuli after chronic mild stress: implications for the psychobiol- effects. Arch Gen Psychiatry 1992; 49:538–544. ogy of depression. Biol Psychiatry 1999; 46: 1624–1633. 56 Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treat- 36 D’Aquila PS, Collu M, Gessa GL, Serra G. The role of dopamine ment-resistant schizophrenic. A double-blind comparison with in the mechanism of action of antidepressant drugs. Eur J Pharma- . Arch Gen Psychiatry 1988; 45:789–796. col 2000; 405:365–373. 57 Moghaddam B, Bunney BS. Acute effects of typical and atypical 37 Vetulani J, Nalepa I. Antidepressants: past, present and future. Eur antipsychotic drugs on the release of dopamine from prefrontal J Pharmacol 2000; 405: 351–363. cortex, nucleus accumbens, and of the rat: an in vivo 38 Carlsson A, Lindquist M. Effect of chlorpromazine and haloperi- microdialysis study. J Neurochem 1990; 54: 1755–1760. dol on formation of 3-methoxytyramine and normetanephrine in 58 Youngren KD, Moghaddam B, Bunney BS, Roth RH. Preferential mouse brain. Acta Pharmacol Toxicol 1963; 20:140–144. activation of dopamine overflow in prefrontal cortex produced by 39 Snyder SH. Catecholamines in the brain as mediators of ampheta- chronic clozapine treatment. Neurosci Lett 1994; 165:41–44. mine . Arch Gen Psychiatry 1972; 27: 169–179. 59 Ashby CR, Wang RY. Pharmacological actions of the atypical anti- 40 Hietala J, Syva¨lahti E, Vuorio K, Ngren K, Lehikoinen P, Ruot- psychotic drug clozapine: a review. Synapse 1996; 24: 349–394. salalainen U et al. Striatal D2-dopamine receptor characteristics 60 Peselow ED, Stanley M. Clinical trials of benzamides in psy- in neuroleptic-naive schizophrenic patients studied with positron chiatry. Adv Biochem Psychopharmacol 1982; 35:163–194. emission tomography. Arch Gen Psychiatry 1994; 51:116–123. 61 Pelissolo A, Krebs MO, Olie JP. Treatment of negative symptoms 41 Dao-Costellana MH, Paille`re-Martinot ML, Hantraye P, Attar-Le´vy in schizophrenia by amisulpride. Review of the literature. Ence- D, Re´my P, Crouzel C et al. Presynaptic dopaminergic function in phale 1996; 22:215–219. the striatum of schizophrenic patients. Schizophr Res 1997; 23: 62 Caley CF, Weber SS. Sulpiride: an antipsychotic with selective 167–174. dopaminergic antagonist properties. Ann Pharmacother 1995; 29: 42 Lindstro¨m LH, Gefvert O, Hagberg G, Hagstro¨m P, Lundberg T, 152–160. Bergstro¨mPet al. Increased synthesis of dopamine in prefrontal 63 Lecrubier Y, Boyer P, Turjanski S, Rein W. Amisulpride Study cortex and striatum in drug-naive schizophrenic patients studied Group. Amisulpride versus and in dysthymia by use of C11-labelled l-DOPA and positron emission tomography and major depression. J Affect Dis 1997; 43:95–103. (PET). Proc Annu Meet ACNP, 36th, 1997, p 290 (abstract). 64 Boyer P, Lecrubier Y, Stalla-Bourdillon A, Fleurot, O. Amisulp- 43 Laruelle M. 2000. Imaging dopamine dysregulation in schizo- ride versus and placebo for the treatment of dysthy- phrenia: implication for treatment. Presented at Workshop Schi- mia. Neuropsychobiology 1999; 39:25–32. zophr: Pathol Bases and Mech Antipsychotic Action, Chicago, 65 Tamminga CA, Gerlach J. New neuroleptics and experimental quoted in Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson antipsychotics in schizophrenia. In: Meltzer HY (ed). Psychophar- M, Carlsson ML, Interactions between monoamines, glutamate, macology: The Third Generation of Progress. Raven Press: New and gaba in schizophrenia: new evidence, Annu Rev Pharmacol York, 1987, pp 1129–1140. Toxicol 2001; 41:237–260. 66 Tagliamonte A, De Montis G, Olianas M, Vargiu L, Corsini GU, 44 Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Gessa GL. Selective increase of brain dopamine synthesis by sulpi- Erdos J et al. Single photon emission computerized tomography ride. J Neurochem 1975; 24:707–710. imaging of amphetamine-induced dopamine release in drug-free 67 Scatton B, Bischoff S, Dedek J, Korf J. Regional effects of neuro- schizophrenic subjects. Proc Natl Acad Sci USA 1996; 93: leptics on dopamine metabolism and dopamine-sensitive adenyl- 9235–9240. ate cyclase activity. Eur J Pharmacol 1977; 44:287–292. 45 Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartol- 68 Harnryd C, Bjerkenstedt L, Gullberg B, Oxenstierna G, Sedvall G, omeis A et al. Schizophrenia is associated with elevated ampheta- Wiesel FA, Time course for effects of sulpiride and chlorpromaz- mine-induced synaptic dopamine concentrations: evidence from ine on monoamine metabolite and prolactin levels in cerebro- a novel positron emission tomography method. Proc Natl Acad spinal fluid from schizophrenic patients. Acta Psychiatr Scand Sci USA 1997; 94:2569–2574. 1984; 69: S75–S92. 46 Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Laruelle 69 Maubrey MC, Jacquot C, Gonidec J, Guez M, Idee JM, Margarit M et al. Increased striatal dopamine transmission in schizo- J. Profil pharmacologique et biochimique de l’amisulpride. Ann phrenia: confirmation in a second cohort. Am J Psychiatry 1998; Psychiatr 1988; 3: 284–297. 155: 761–767. 70 Chivers JK, Gommeren W, Leysen JE, Jenner P, Marsden CD. Com- 47 Grace AA. Phasic versus tonic dopamine release and the modu- parison of the in-vitro receptor selectivity of substituted benza-

Molecular Psychiatry Substituted benzamides in depressive states L Pani and GL Gessa 253 mide drugs for brain neurotransmitter receptors. J Pharm Pharma- 92 Devoto P, Flore G, Pani L, Gessa GL, Evidence for co-release of col 1988; 40: 415–421. noradrenaline and dopamine from noradrenergic neurons in the 71 Ogren SO. Selective dopamine D2 receptor antagonists with an cerebral cortex. Mol Psychiatry 2001; 6:657–664. atypical neuroleptic profile. Clin Neuropharmacol 1992; 15 93 Khan ZU, Koulen P, Rubinstein M, Grandy DK, Goldman-Rakic (Suppl 1): 462A–463A. PS. An astroglia-linked dopamine D2-receptor action in prefrontal 72 Chouinard G. Early phase II clinical trial of remoxipride in treat- cortex. Proc Natl Acad Sci USA 2001; 98: 1964–1969. ment of schizophrenia with measurements of prolactin and neuro- 94 Selemon LD, Lidow MS, Goldman-Rakic PS. Increased volume leptic activity. J Clin Psychopharmacol 1987; 7:159–164. and glial density in primate prefrontal cortex associated with 73 Lindstrom L, Besev G, Stening G, Widerlov E. An open study of chronic antipsychotic drug exposure. Biol Psychiatry 1999; 46: remoxipride, a benzamide derivative, in schizophrenia. Psycho- 161–172. pharmacology 1985; 86:241–243. 95 Vallone D, Ricetti R, Borrelli E. Structure and function of dopam- 74 Lund Laursen A, Gerlach J. Antipsychotic effect of remoxipride, ine receptors. Neurosci Biobehav Rev 2000; 24:125–132. a new substituted benzamide with selective antidopaminergic 96 Wadworth AN, Heel RC. Remoxipride. A review of its pharmaco- activity. Acta Psychiatr Scand 1986; 73:17–21. dynamic and pharmacokinetic properties, and therapeutic poten- 75 McCreadie RG, Morrison D, Eccleston D, Gall RG, Loudon J. An tial in schizophrenia. Drugs 1990; 40:863–879. open multicentre study of the treatment of florid schizophrenia 97 Scatton B, Claustre Y, Cudennec A, Oblin A, Perrault G, Sanger with remoxipride. Acta Psychiatr Scand 1985; 72: 139–143. DJ et al. Amisulpride: from animal pharmacology to therapeutic 76 Willner P. Animal models of depressions: validity and appli- action. Int Clin Psychopharmacol 1997; 12 Suppl 2: S29–S36. cation. In: Gessa GL (ed). Neurobiology Treatment. Raven Press: 98 Seeman P, Tallerico T. Antipsychotic drugs which elicit little or New York, 1995; pp 19–41. no parkinsonism bind more loosely than dopamine to brain D2 77 Papp M, Wieronska J. Antidepressant-like activity of amisulpride receptors, yet occupy high levels of these receptors. Mol Psy- in two animal models of depression. J Psychopharmacol 2000; 14: chiatry 1998; 3:123–134. 46–52. 99 Goldman-Rakic PS, Lidow MS, Gallager DW. Overlap of dopami- 78 Drago F, Arezzi A, Virzi A. Effects of acute or chronic adminis- nergic, adrenergic, and serotoninergic receptors and comp- tration of substituted benzamides in experimental models of lementarity of their subtypes in primate prefronal cortex. J Neuro- depression in rats. Eur Neuropsychopharmacol 2000; 10:437–442. sci 1990; 10: 2125–2138. 79 Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carls- 100 Lidow MS, Goldman-Rakic PS, Gallager DW, Rakic P. Distribution son ML, Interactions between monoamines, glutamate, and GABA of dopaminergic receptors in the primate cerebral cortex: quanti- in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol tative autoradiographic analysis using 3H raclopride, 3H spip- 2001; 41:237–260. erone and 3H SCH23390. Neuroscience 1991; 40: 657–671. 80 Lahti AC, Weiler MA, Corey PK, Lahti RA, Carlsson A, Tamminga 101 Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O CA. Antipsychotic properties of the partial (-)- et al. Decreased prefrontal dopamine D1 receptors in schizo- 3-(3-hydroxyphenyl)-N-n-propylpiperidine (preclamol) in schizo- phrenia revealed by PET. Nature 1997; 385:634–636. phrenia. Biol Psychiatry 1998; 43:2–11. 102 de Kuyser J, de Backer JP, Vauquelin G, Ebinger G. The effect of 81 Svensson K, Hjorth S, Clark D, Carlsson A, Wikstro¨m H, Anders- aging on the D1 dopamine receptors in human frontal cortex. + + son B et al.( )-UH 232 and ( )-UH 242: novel stereoselective DA Brain Res 1990; 528:308–310. receptor antagonists with preferential action on autoreceptors. J 103 Suhara T, Fukuda H, Inoue O, Itoh T, Suzuki K, Yamasaki T et Neural Transm 1986; 65:1–27. al. Age-related changes in human D1 dopamine receptors meas- 82 Sonesson C, Lin CH, Hansson L, Waters N, Svensson K, Carlsson ured by positron emission tomography. A et al. Substituted (S)-phenylpiperidines and rigid congeners as 1991; 103:41–45. preferential dopamine autoreceptor antagonists: synthesis and 104 Salthouse TA. Working-memory mediation of adult age differ- structure-activity relationships. J Med Chem 1994; 37: 2735–2753. ences in integrative reasoning. Mem Cogn 1992; 20:413–423. 83 Jimerson DC. Role of dopamine mechanisms in affective dis- 105 Castner SA, Goldman-Rakic PS. Profound cognitive impairments orders. In: Meltzer HY (ed). Psychopharmacology: The Third Gen- in non-human primates exposed to amphetamine. Soc Neurosci eration of Progress. Raven Press: New York, 1987 pp 505–511. Abstr 1999; 25: 627.6. 84 Knable MB, Weinberger DR. Dopamine, the prefrontal cortex and 106 Lidow MS, Williams GV, Goldman-Rakic PS. The cerebral cortex: schizophrenia. J Psychopharmacol 1997; 11:123–131. a case for a common site of action of antipsychotics. Trends 85 Cha JH, Kosinski CM, Kerner JA, Alsdorf SA, Mangiarini L, Davies Pharm Sci 1998; 19:136–140. SW et al. Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington dis- 107 American Psychiatric Association. Diagnostic and Statistical ease . Proc Natl Acad Sci USA 1998; 95: 6480–6485. Manual of Mental Disorders, Fourth Edition, American Psychi- 86 Wise RA. Neurobiology of addiction. Curr Opin Neurobiol 1996; atric Association: Washington DC, 1994, pp 276–277. 6: 243–251. 108 Serretti A, Jori MC, Casadei G, Ravizza L, Smeraldi E, Akiskal H. 87 Gothham AM, Brown RG, Marsden CD. ‘Frontal’ cognitive func- Delineating psychopathologic clusters within dysthymia: a study tion in patients with Parkinson’s ‘on’ and ‘off’ levodopa. of 512 out-patients without major depression. J Affect Disord Brain 1988; 111:299–321. 1999; 56:17–25. 88 Volkow ND, Gur RC, Wang GJ, Fowler JS, Moberg PJ, Ding YS et 109 American Psychiatric Association. Diagnostic and Statistical al. Association between decline in brain dopamine activity with Manual of Mental Disorders. Fourth Edition, American Psychi- age and cognitive and motor impairment in healthy individuals. atric Association: Washington DC, 1994, pp 345–346. Am J Psychiatry 1998; 155:344–349. 110 Leonard BE. Evidence for a biochemical lesion in depression. J 89 Brozoski T, Brown RM, Rosvold HE, Goldman PS. Cognitive defi- Clin Psychiatry 2000; 61 Suppl 6: 12–17. cit caused by regional depletion of dopamine in prefrontal cortex 111 Lambert G, Johansson M, Agren H, Friberg P. Reduced brain nore- of rhesus monkey. Science 1979; 205: 929–932. pinephrine and dopamine release in treatment-refractory depress- 90 Mu¨ ller U, von Cramon DY, Pollman S. D1- versus D2-receptor ive illness: evidence in support of the catecholamine hypothesis modulation of visuospatial in humans. J Neuro- of mood disorders. Arch Gen Psychiatry 2000; 57:787–793. sci 1998; 18: 2720–2728. 112 Malmberg A˚ , Jerning E, Mohell N. Critical reevaluation of spip- 91 Goldman-Rakic PS, Muly III EC, Williams GV. D1 receptors in erone and benzamide binding to dopamine D2 receptors: evidence prefrontal cells and circuits. Brain Res Rev 2000; 31:295–301. for identical binding sites. Eur J Pharmacol 1996; 303:123–128.

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