This article examines the analogy between military tactics and the goal-directed functioning of appetites that Leibniz used both in the Discourse on Metaphysics (1686) and in his controversy with Stahl (1710). In so doing, my purpose is threefold: 1/ to question the unity of the concept of appetite in Leibniz; 2/ to show that Leibniz's notion of the explanatory role of appetites casts doubt on the traditional conflation between appetite and desire for self-preservation; 3/ to demonstrate that self-conscious appetites cannot be regarded as specific final causes of psychophysiological phenomena.

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"Appetite" is a traditional notion that allows Early Modern physicians and philosophers to account for the final causality between the soul and its body. One single notion, that of appetite, covers wildly different cases: by virtue of a natural appetite, the plant attracts nutrients; the soul of an animal has the appetite of hunger, which causes its body to seek food; humans themselves may carry out a series of actions by "rational appetite," that is to say, by free will. 2 Appetite usually refers either to 1/ a certain capacity to seek out what seems good or agreeable and reject what seems bad, or 2/ to the representation of those things that are perceived as desirable or repugnant.

Leibniz's own notion of appetite, or "appetition," apparently fits into this general framework. According to him, "souls act according to the laws of final causes, through their appetitions, ends, and means. Bodies act according to the laws of efficient causes or of motion. And the two kingdoms, that of the efficient [causes] and that of the final causes, are in harmony with each other." 3 Appetitions are strivings towards ends that result in the seeking of means.

Even if Leibniz does not accept the principle of a direct, extrinsic causation between motions and appetites, the harmony between the two accounts well for the behavior of living beings, which is usually explained by the power that a soul exerts over its body. In both cases, the notion of appetite justifies accounting teleologically for the actions of living beings.

Accordingly, one could expect that over the course of his dispute with Georg Ernst Stahl, Leibniz would express his agreement with the notion that the soul's appetites might enable the physician to account for the functioning of the body, especially in cases in which anatomical structures and small organic motions fail to explain it. Surprisingly enough, however, Leibniz denies the explanatory value of conscious appetites regarding the functioning of the body. For example, the appetite or desire for self-preservation would have no explanatory value with respect to the physiological process of nutrition. To illustrate this point, Leibniz develops an analogy between military tactics and the goal-directed functioning of appetites.

In this article, I study the analogy with war, which Leibniz used both in the Discourse on Metaphysics (1686) and in his controversy with Stahl (1710). In so doing, my purpose is threefold: 1/ I want to question the unity of the concept of appetite in Leibniz; 2/ I want to show that Leibniz's notion of the explanatory role of appetites casts doubt on the traditional conflation between appetite and desire for self-preservation; 3/ I want to show that selfconscious appetites cannot be regarded as specific final causes of psychophysiological phenomena.

Appetite: wise strategy or unconscious inclinations?

In article 19 of the Discourse on Metaphysics (1686), Leibniz uses the analogy with war to illustrate the usefulness of final causes: it is unreasonable to introduce a supreme intelligence as orderer of things and then, instead of using his wisdom, use only the properties of matter to explain the phenomena. This is as if, in order to account for the conquest of an important place by a great prince, a historian were to claim that it occurred because the small particles of gunpowder, set off by the contact of a spark, escaped with sufficient speed to push a hard and heavy body against the walls of the place, while the little particles that make up the brass of the cannon were so firmly interlaced that this speed did not separate them, instead of showing how the foresight of the conqueror enabled him to choose suitable means and times and how his power overcame all obstacles (A VI-4, p. 1561; trans. AG, p. 53) The prince at war is like God creating the world: he intelligently chooses means and intermediary ends according to his original purpose. Consequently, in order to explain these means, it is better to look at his primary goal. The comparison with military strategy aims at justifying the consideration of perfection and fitness in the explanation of natural phenomena. In this case, the explanandum is the structure of bodies, and the explanans God's wisdom. But this explanation of natural phenomena is not the only case in which Leibniz recommends appealing to final causes. In article 20, Leibniz, with reference to Plato's Phaedo, accounts for Socrates' actions also by referring to the decisions of an intelligent agent. Indeed, one cannot explain why Socrates swallowed hemlock by referring to the small movements of his bones and nerves. The true explanation of Socrates' behavior flows from Socrates' own judgment, which makes him prefer swallowing hemlock to living in exile. In this second example, the explanandum is a behavior, that is, a complex set of human actions, which are both observable (and as such belong to physical phenomena) and related to a conscious plan that can be shared and communicated. The explanans is the rational decision, or will, of a human being, Socrates. Notwithstanding these differences, wise decisions of rational agents provide in both cases explanations for observable phenomena which are more intelligible than explanations in terms of material necessity or efficient causation.

In his defense of the use of final causes in articles 19 and 20 of the Discourse on Metaphysics, Leibniz does not mention the notions of will, volition, or appetition. As a matter of fact, the notion of appetite is quite rare in Leibniz's early texts. Leibniz uses the notion of appetite as the opposite of "aversion" in lists of definitions or in annotations from the 1670s. 4 But it is only in the New System of the Nature and Communication of Substances (1695) that souls or soul-like entities are said to be endowed with two fundamental properties: perception and appetition. From that work on, the notion of "appetition" will be conceived as a generic term that refers to unconscious natural appetites and animal tendencies toward new pleasures, as well as to intelligent volitions, also described as rationales appetitus. In the most famous presentations of Leibniz's system, where the notion of appetition appears, he neither defines it, nor comments on it: he only dogmatically presents it as one of the two key components of his own "pneumatics", or science of the soul, by means of which it would be possible to account economically for all kinds of feeling or affects. The notion of appetition is detailed only in Leibniz's correspondence and controversial exchanges. Leibniz first discusses it in his exchanges with Pierre Bayle, following the publication of the New System. In this context, the notion of appetite gains in importance. On the one hand, Leibniz now speaks of the "law of appetites" as parallel to, and harmonious with, the laws of motions which rule over physical causation. 5 The increasing importance of appetites is thus partly due to the development and spelling out of the hypothesis of pre-established harmony in the context of discussion with the "Cartesian" philosophers 6 . On the other hand, Leibniz now emphasizes the existence of an infinite number of "unconscious inclinations or appetitions," which explain why the soul often acts without knowing what it does, and why it often fails to enjoy new pleasures. 7 Indeed, Pierre Bayle did not understand how in a Leibnizian world in which the soul always acts spontaneously, the series of internal actions could make a dog's soul feel pain immediately after having felt pleasure. To explain his counter-intuitive claims about the spontaneity of the soul and to account for involuntary actions, Leibniz resorts to the notion of appetite: unconscious inclinations and appetites concur with conscious volitions, producing our perceptions; when these small appetites are stronger than our rational volitions, they trigger perceptions that thwart the conscious desires and anticipations of the soul. Accordingly, what explains the inner changes in the soul of the dog is less its conscious global appetite of eating, or of enjoying new pleasures, than the millions of tendencies of which the dog is not aware. In this case, the notion of appetite no longer refers to conscious decisions and wise strategies; it rather refers to secret and concealed motives. If there is any teleology here, it is a very different kind of teleology from the planned and intelligent strategy of a war prince.

One finds more or less the same use of the notion of appetite in the correspondence with Hartsoeker. In this correspondence too, the notion successively appears on two levels. 1/ It first appears at what I would call the esoteric level of the metaphysical doctrine: at this level, appetite is defined by Leibniz as the principle of change from one perception to another according to an order that is in harmony with the succession of bodily motions, as if the appetite were the cause of such or such motion in the body. 2/ When Leibniz has to explain a bit more how the soul's appetites and bodily motions correspond to each other, the concept of appetite is further explicated at a level that I would call a reactive, or exoteric level of explanation, appearing in cases in which Leibniz proposes specific answers to specific criticisms.8 At this level, appetites emanate from an unconscious dynamics according to which agents are led to behave in ways opposite to their apparent purposes and own good. The problem is that such an unconscious dynamics, which by definition is concealed from the agent and possibly from witnesses, might not play the same obvious explanatory role as the wise decisions of free agents that are mentioned in the Discourse on Metaphysics. In other words, these two levels seem to conflict with each other. Such an amphibology of the notion of appetite appears clearly in the Leibniz-Stahl controversy.

The war analogy in the Leibniz-Stahl controversy

At the beginning of the controversy, Leibniz reminds Stahl of the principal components of his own system. 9 After having pointed out the necessity of admitting final causes, he explains how his own hypothesis of pre-established harmony allows him to use common-sense vocabulary and to account for common-sense beliefs. According to Leibniz's hypothesis, for example, no wish of the soul really causes a voluntary motion in the body; and reciprocally, speaking with metaphysical rigor, no bodily disorder can cause passion in the soul. But as a Copernican may say that the sun is rising, it is also possible to say that a motion of the body is voluntary whenever it occurs in agreement with noticeable perceptions or conscious decisions of the mind. Reciprocally, it is possible to say that the mind is affected by its body when bodily changes best account for the confused perceptions of the mind that occur concomitantly: I showed, I say, that certain concealed truths of great importance that can be elicited by the consideration of final causes would be difficult to elicit from efficient causes, since the ends of nature are sometimes manifest, while its efficient means are hidden. [...] Thus it comes about that, from the intention of the Author and from the appetite of the soul, effects may be foreseen whose proximate efficient causes in the body may be judged to be insufficiently explained [...]. From this connection with the body, moreover, and particularly with the fetus, of the sensations and affections that are expressed and appear more distinctly in the soul, it may be understood that confused perceptions and hidden appetites concur and agree no less with the internal functions of the body [intestinis functionibus corporis] that we call "involuntary", and with the entire formation of the fetus, even if it is not noticed. Certainly, when magnitude renders a thing sensible, this does not change its nature. But those motions are not incorrectly called "voluntary" that are connected to more distinctly conscious appetites, when we notice that our soul adapts means to ends, while in all other motions the appetite proceeds toward its ends by means that we do not notice. Consequently, those actions are properly called "voluntary" that we do deliberately and are conscious of. 10 Let us rephrase this passage:

1. According to the beginning of the citation, final causes are sometimes more manifest than efficient causes, which are often hidden. This is exactly the argument of the Discourse on Metaphysics: under certain conditions, ends may be more obvious and explanatory than efficient proximate causes and mechanical details. Ends enable us to anticipate future effects; they also enable us to more straightforwardly understand present effects. There is thus a clear heuristic gain from ends, or final causes. 2. Nevertheless, the mind-body connection is not weaker in the cases where the perceptions or appetites remain hidden from us. In other words, appearances may be misleading: we do not always perceive the appetite that is the mental correlate of a motion of our body, but there should always be such a mental correlate. According to this second point, the appetite is not necessarily an obvious final cause -it may be hidden and unconscious: as such, it would have no specific explanatory role to play. 3. Still, there is an apparent specificity of voluntary motions, which seem to obey our conscious appetites. Accordingly, we could explain those so-called voluntary motion by identifying the ends that are foreseen by the mind, i.e. "conscious appetites," with the final causes of these motions. In other words, the apparent dissymmetry between voluntary and involuntary motions would justify a certain kind of explanatory specificity, or a specific scheme of explanation for voluntary motions only. These three arguments together are a little bit puzzling. On the one hand, appetites are regarded as legitimate final causes. On the other hand, their explanatory role is not systematic, and depends on the fact that these appetites are conscious. And yet, the fact that appetites are sometimes conscious and sometimes unconscious does not change anything in the real production of phenomena, nor in the systematic connection, or harmony, between phenomena. Hence, Leibniz seems alternatively to promote and dismiss the appeal to appetites in the explanations of bodily motions.

Leibniz's reluctance to refer to appetites as final causes of bodily motions is confirmed by the second use of the war analogy:

Since perceptions and appetites of the soul respond to all vital motions of an animal, it is necessary that these truly be many; since indeed the multitude of vital motions is great, it is likewise necessary that they be confused or obscure so that they, on account of multitude and habit, will not be noticed by us [...]. It can indeed be said that the end is simple, namely, self-preservation; and that the means to it, generally considered, are few, namely, appropriate nutrition and secretion. But this is as if one argued with a certain military leader, maintaining that nothing would be easier than to put an end to the war. He would say, in fact, that it is simply a matter of the Gauls being struck down, and then of entering into Lutetia. The goal is simply peace; the means are no less simple: to overcome the enemies in battle and to take their principal cities. But how many things are here required for the means of means? Thus, likewise, innumerable partial vital motions are required for nutrition and secretion to take place properly; and to all these singular motions of the body, appetites correspond in the soul, even though we are not aware of them. 11

What is striking is the fact that the war analogy is used in the exact opposite way from its use in the Discourse on Metaphysics: here, the aim no longer is to legitimate the appeal to wise voluntary decisions as final ends of noticeable phenomena; the aim is rather to balance the obvious explanatory role of conscious appetites conceived as final causes by the existence of innumerable unconscious appetites and intermediary perceptions of means. Conscious intentions are just the tip of the iceberg; they conceal the internal dynamics needed to understand the functioning of the body, the functioning of the soul, and even the relationships between the two. The plan of the military leader implies not only an initial and global aim, but also means, and means of means, and even means of means of means -since it is always possible to further analyze the sequence of perceptions or appetites and the sequence of bodily motions that contribute to produce the noticeable action or effect that we seek to explain.

According to this passage, to claim, as Stahl does, that the end of the soul is the conservation of the body, is not informative or explanatory at all. This end, the conservation of the body through nutrition, is too general to be informative, even if one may consider that it allows in some cases to anticipate the behavior of humans and animals. This passage thus offers good reasons not simply to regard appetites as expressions of a univocal striving for self-preservation.

Appetites are more specific than that. They are tendencies towards certain means.

In the Discourse on Metaphysics, the war analogy justifies the use of conscious aims as final causes: this analogy emphasizes the global strategy and final aim of the military leader. By definition, such an aim is simple, obvious, and known to the agent. In the Leibniz-Stahl controversy, the war analogy rather emphasizes the dreadful complexity of military tactics. Tactics implies a multitude of secondary means that are not entirely obvious, even for the agent, who is not always able to grasp them in one single glance. The notion that appetites are more numerous than one can imagine and remain partly hidden from us raises at least three questions which will be addressed subsequently.

Appetite as a motus primo primi?

A first problem raised by the war analogy is the difficulty of bringing together, term by term, the sequence of appetites and the sequence of physical motions. According to the Leibniz-Stahl controversy, we have the following sequence: the perception of the end, or the appetite to preserve oneself, triggers the appetite for means (nutrition), which in its turn triggers the appetite for means of means (swallowing such food, etc.). This psychic sequence leads from a global intention, or conscious appetite, to the innumerable smaller appetites that compose this conscious appetite. In other words, the sequencing goes from large-scale to small-scale. But how are we to put together this analytic decomposition of conscious appetites and the efficient sequence of physical motions? Indeed, according to other Leibnizian texts, we get another kind of sequencing, which is harmonious with that of thoughts:

The representation of the present state of the universe in the dog's soul produces in it the representation of the subsequent state of the same universe, just as in the things represented the preceding state actually produces the subsequent state of the world. In a soul, the representations of causes are the causes of the representations of effects. And since this subsequent state of the world includes the blow on the dog's body, the representation of that subsequent state in its soul includes the pain which corresponds to that blow. 12 In the body, the cause (the blow) triggers the effect (hematoma), which triggers another effect (the dog's flight); while in the soul the cause (the representation of the blow) triggers the effect (the perception of pain), which triggers another effect (the appetite or instinct to flee 13 ). The two causal series, physical and psychic, correspond exactly to each other. In this case, the appetite ends the series of perceptions. Appetite is a result, not an initial impulse, or a motus primo primi, as seems to be the case in the war analogy 14 . The problem partly arises from the fact that when Leibniz insists on the concomitance between the soul and its body, as is the case in his replies to Bayle, he rather speaks of "perceptions." But if we introduce appetites, we do not know where exactly their place is in the whole series. Appetitions are considered the efficient causes of new perceptions, since they are often defined as tendencies toward new perceptions; but it happens that some very confused efforts or appetitions are said to result from small "imperceptible" perceptions. Several commentators have recently emphasized this difficulty. Julia Jorati has shown that the notion of appetite seems sometimes to be redundant with other key notions of Leibniz's philosophy of mind. 15 Indeed, it is somehow difficult to understand the respective causal and explanatory roles of perceptions and appetites in Leibniz's philosophy of mind: Leibnizian perceptions themselves trigger new perceptions according to the immanent force, or law of inner change, of souls or soul-like entities; consequently, what is the specific role of appetites, which are supposed to be the dynamic elements in this framework? Before Jorati, Jonathan Bennett had pointed out that the more Leibniz was led to explain in detail the functioning of appetites, the less these appetites seemed teleological. As he wrote about a passage from the New Essays:

A worse trouble [...], is that the picture Leibniz is drawing here does not seem teleological; it is too much like mere itch-scratching [...] [M]etaphysics says that each monad falls within the realm of final causes, but all Leibniz is offering us here are spurs, springs, imbalances -efficient causes. 16 Though I do not agree with Bennett's general view in this paper, 17 I think that his diagnosis on the very notion of appetite in the New Essays is correct: appetites do not always introduce an obvious teleological dimension in explanations, especially when Leibniz develops the notion that countless small appetites and inclinations partly account for the behavior of living beings.

The heuristic role of pre-established harmony

From the Discourse on Metaphysics to his answers to Father Tournemine, Leibniz explains that the hypothesis of pre-established harmony allowed him to naturally account for phenomena, or more precisely to account for the noticeable correlation between certain physical and psychic 13 On this assimilation, see Controvérsia, p. 27: "appetite (in which I include, depending of circumstances, the instinct to flee)". 14 GP V, p. 175. 15 "Why Monads Need Appetites," in Für unser Glück oder das Glück anderer': Vorträge des X. Internationalen Leibniz-Kongresses Hannover, 18.-23. Juli 2016, ed. Wenchao Li, Hildesheim: Olms, 2016, vol. 5, p. 121-29. 16 "Leibniz's Two Realms", in Rutherford and Cover eds., Leibniz: Nature and Freedom, 2005, p. 135-155, here p. 148. 17 See J. McDonough, "Leibniz's Two Realms Revisited", Noûs, 42-4, 2008, p. 693-696, here p. 690. phenomena. 18 In other words, pre-established harmony aims at explaining what is noticeable. And yet, during the Leibniz-Stahl controversy, pre-established harmony is rather used to show the existence of an uninterrupted series of psychic events, most of which remain completely hidden from the agents. Indeed, according to the analogy with military tactis, some confused and hidden appetite would to correspond to each small organic motion in the body, and conversely. In this last case, pre-established harmony encourages reconstructing the whole series of secret appetites in harmony with the internal functions or struggles within the body. The explanandum of pre-established harmony has changed: the explanandum no longer is the striking correspondance between some decisions of the mind and some voluntary motions of the body; it is rather the apparent break down of this correlation which Leibniz relates to the fact that the constant correlation between thoughts and motions remains in most cases hidden from us. On the one hand, pre-established harmony is no longer mentioned to justify commonsense impressions, nor to interpret them according to the "metaphysical rigor". Pre-established harmony is rather mentioned to balance our conscious motives with unconscious appetitesthat is to say, to relativize the informative nature of our conscious motives. On the other hand, what has an explanatory value here no longer is some distinct and noticeable thoughts and appetites; on the contrary, as has been noted by François Duchesneau, it is the small internal motions of the body to which, by analogy, and according to pre-established harmony, hidden appetites correspond. 19 To put it schematically, the explanation does not go from the soul to the body, as is usually the case for voluntary motion, when an intention of the soul explains a motion of the body. The explanation goes from the body to the soul. The series of bodily motions entices us to reconstruct by analogy the continuous series of perceptions and appetites that are joined by means of imperceptible links. Instead of resorting to noticeable psychic events in cases in which the detail of bodily mechanisms does not seem to be informative enough, we have to use what we know of this bodily mechanism as a model for dividing our conscious appetites into a multiplicity of unconscious appetites. By analogy, the anatomy of bodies sheds a new light on what turns out to be an internal and secret strategy of the soul.

Appetites as final causes?

In these conditions, is it still possible to say that the appetite has explanatory value with respect to bodily motions? And is it still possible to say that psychic events -either perceptions or appetites -provide final causes that allow us both to foresee and to better explain physical events? To be sure, according to the dogmatic esoteric presentation of Leibniz's hypothesis, appetites are final causes. However, as soon as Leibniz argues about the legitimate way of explaining the motions of our own body, he rather discourages regarding distinct appetites and conscious plans as final causes. We could object that the Leibniz-Stahl controversy does not really reflect Leibniz's opinion. But we can find exactly the same analysis of appetites in the correspondence with Hartsoeker: A l'égard de l'Harmonie préétablie entre les modifications de l'âme et du corps, et l'exécution de nos appétits par les organes, il faut que les appétits et par conséquent les perceptions dont ils naissent, aillent à un parfait détail de tout ce qui se fait dans les organes, à fin que ces appétits soient exécutés, ce qui profiterait s'il nous était possible de faire l'analyse de nos perceptions confuses. Et autrement sans ce détail, ce ne serait point un appétit parfait et entier de tout cet objet, mais seulement quelque chose d'approchant. Et comme notre entendement et par conséquent notre volonté n'est point capable de ce détail, notre simple volonté (si l'appétit va à la fin sans aller aux moyens et moyens des moyens) n'est pas un appétit que le corps soit obligé de suivre et d'exécuter ; il ne l'est que dans les mouvements intérieurs volontaires, non empêchés, où l'appétit confus seconde la volonté ou l'appétit distinct, par un parfait détail, les organes étant faits exprès pour cela. Cependant nos mouvements intérieurs involontaires ne laissent point de répondre à nos appétits confus et inaperceptibles, mais ces mouvements dépendent aussi peu de l'empire de la volonté que ces appétits dépendent peu de notre entendement [...]. Si ces méditations paraissent un peu obscures, ce n'est qu'à cause de leur profondeur et de l'attention dont elles ont besoin sur tout quand on ne les peut exposer qu'en abrégé tel que demande l'étendue d'une lettre. 20 As soon as Leibniz is led to detail the teleological value of the appetite in the framework of his pre-established harmony, he is also led to admit that things are "more complicated than one might think at a first sight." Appetites as conscious wishes rarely suffice for causing voluntary motions if they are not helped by secondary appetites for means which are in harmony with internal motions. Consequently, teleological explanations seem neither obvious nor easy. Leibniz gives Hartsoeker good reasons not to regard appetites as final causes. First, he provides reasons not to regard them as those final causes that were promoted by means of the war analogy in the Discourse on Metaphysics -that is to say, as explanations of physical phenomena that would be more intelligible, obvious and straightforward than explanations in terms of small mechanical motions. Second, Leibniz's clarifications of the notion of appetite, whether in the Leibniz-Stahl controversy or in the letters to Hartsoeker, challenge the usual teleological understanding of the notion. In Stahl's view for example, which is in accordance with the traditional view in medicine, appetite is by definition something noticeable that really causes actions in situations that are beyond simple automatic bodily motions. By definition, appetite, that is, the desire toward an end, is "distinctly conscious" and accounts for means that are very few and simple. As Stahl puts it: the soul wants life, which is lasting conservation of its body, for it not only pertains to the soul that the body be and endure (I mean physically), but it pertains to it absolutely [...] Now since the ends are not very many in vital affairs, the means are not an immense multitude either, but rather the former are very few, and the latter certainly not many [...]. 21 The teleological explanatory value of appetite usually requires admitting a real psychophysiological causality that Leibniz denies. Denying such a psychophysiological causality, and acknowledging instead the causality of a multitude of secret appetites as Leibniz does, leads to depriving appetites of their common teleological explanatory value with respect to bodily functions. As we have seen in article 19 of the Discourse on Metaphysics, Leibniz grants a crucial role to "large-scale final causes that are traceable back to God" 22 , or to teleological principles rooted in God's choice in creating the world. But we can still wonder if it leaves any decisive and irreplaceable explanatory power for small-scale final causes. In any case, such small-scale final causes of organic motions are not identified with the conscious appetites of animals and human beings -for example, seeking pleasure, happiness, or selfpreservation.

Conclusion

The different uses of the war analogy cast doubt on the generic identity between conscious volitions and secret appetites, which cannot have the same explanatory value in Leibniz's philosophy. In the Discourse on Metaphysics, this analogy indicates that men's conscious ends and global strategies are legitimately conceived of as final causes: these conscious ends allow us to explain phenomena that are not easily rendered intelligible through mechanical causes. On the contrary, the war analogy in the Leibniz-Stahl controversy implies regarding conscious ends and general goals as psychic elements that are either not explanatory, or partially misleading. The aim of the military leader (to win the war) does not really explain the series of actions that will lead to his success or failure (his tactics and his reactions to events that do not entirely depend upon him). There is only partial coincidence between the initial goal of the military leader and the series of actions that he will successively trigger. With the analogy between the psychophysiological functioning of the human body and military tactics, Leibniz wants to show that the soul's appetite for self-preservation is not the final cause of organic motions. The desire for self-preservation has no explanatory value at all. It is far too general to explain anything. But in so doing, Leibniz particularly insists on the fact that most of our appetites remain hidden and, above all, do not depend upon our will. Accordingly, we might first wonder if the secret appetites of our mind that correspond one by one to the small organic motions of our body belong to the same kind of mental states as the conscious and intelligent aims promoted in the Discourse on Metaphysics -more importantly, do they have the same epistemological use? Second, we might wonder what is the right scale of teleological explanations for Leibniz with regard to the psychophysiological functioning of living beings.

Institut d'histoire des représentations et des idées dans les Modernités, Unité Mixe de Recherche n° 5317, CNRS Université de Lyon (CNRS, ENS de Lyon, Université Lyon

2, Université Saint-Etienne, Université Clermont Auvergne, université Lyon 3). I am grateful to François Duchesneau and Layla Roesler for their reading and comments. 2 For such a conception, see The Physiologia of Jean Fernel (1567), Book 5, chap. 9, transl. John M. Forrester, Philadelphia: American Philosophical Society, 2003, p. 343; see also Henricus Regius, Medicina et praxis medica edition tertia, Trajecti ad Rhenum, ex Officina Theodori abAckersdijck, 1668, p. 23. 3 Monadology, § 79, GP VI, p. 620, in Philosophical Essays, ed. and transl. Ariew and Garber, Indianapolis: Hackett 1989, p. 223 (hereafter cited AG).

See for example AVI-4, p. 1398 (Definitiones cogitationesque metaphysicae) or p. 1417 (De affectibus).

Unpublished comments on Bayle's Dictionary (1702), "Rorarius", note L, GP IV, p. 545 ("les lois de l'appétit" are translated by "laws of desire" in Leibniz's New System and Associated Contemporary Texts, ed. and trans. By R. S. Woolhouse and Richard Francks, Oxford, Clarendon Press, 1997, p. 101 -hereafter cited New system).

I use the term 'Cartesian' as a convenient label. By 'Cartesians' I refer only to those French philosophers who, in the late seventeenth century, discussed and developed Descartes' metaphysics in new directions (and particularly in an occasionalist one).

New System, p. 104, GP IV, p. 540 ("J'ay déja montré plus d'une fois que l'ame fait beaucoup de choses sans savoir comment elle les fait, lorsqu'elle le fait par le moyen des perceptions confuses et des inclinations ou appetitions insensibles dont il y en a tousjours un grandissime nombre et dont par consequent il est impossible que l'ame s'apperçoive, ou qu'elle puisse les demeler distinctement").

See Letter to Hartsoeker, 1715, GP III, p. 510, § 22, cited below.

On this controversy, see François Duchesneau, "Leibniz et Stahl: divergences sur le concept d'organisme," Studia Leibnitiana, 27:2, 1995, pp. 185-212. More generally, for the Leibnizian notion of living bodies, see Leibniz. Le vivant et l'organisme, Paris, Vrin, 2010.

Extract from 'Comment on an article in the Mémoires de Trévoux for March 1704' (1708), GP VI, p. 595, trans. in New System, p. 249: "My aim was to explain naturally what they explain by perpetual miracles, and in doing so I attempted only to give an explanation of the phenomena, that is to say, of the relation we perceive between the soul and the body."

Art. cit., p.

201: "La zone des phénomènes de perception et d'appétition conscientes fournit matière à une investigation empirique des dispositifs et processus sensitivo-moteurs corrélatifs des représentations de l'âme. Et, en vertu des principes architectoniques de continuité et de l'identité des indiscernables, il est possible de prolonger cette investigation empirique en recourant à des hypothèses analogiques sur les corrélations entre mécanismes physiologiques et représentations infraconscientes, ce que Leibniz qualifie de petites perceptions et d'appétitions se transformant en instincts."Raphaële Andrault, « The internal struggles of the appetite : a secret teleology ? », dans A. Cardoso et M. Mendonça (dir.),Leibniz-Stahl. Controvérsia sobre vida, organismo et teleologia, Lisboa, Húmus, 2022, p. 25-40. Version auteur.

Leibniz to Hartsoeker, GP III, p. 510, § 22.

Stahl's Enodations, XX, in Controvérsia, p. 149. On this point, see Duchesneau,


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MD PhD, the FACE-SZ Fondamental

Llorca Pm

Major depression, sleep, hostility and body mass index are associated with impaired quality of life in schizophrenia. Results from the FACE-SZ cohort

Keywords: psychiatry, quality of life, schizophrenia, sleep quality, hostility, major depression, weight

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

SZ is still associated with deeply impaired QoL despite decades of research focusing on residual psychotic/mood symptomatology, impaired daily functioning, high insight into illness and internalized stigma [START_REF] Roux | Mediation Analyses of Insight, Quality of Life, Depression, and Suicidality: Results From the FACE-SZ Cohort[END_REF][START_REF] Çapar | Effect of internalized stigma on functional recovery in patients with schizophrenia[END_REF][START_REF] Lysaker | Insight in schizophrenia spectrum disorders: relationship with behavior, mood and perceived quality of life, underlying causes and emerging treatments[END_REF][START_REF] Andrianarisoa | Childhood trauma, depression and negative symptoms are independently associated with impaired quality of life in schizophrenia. Results from the national FACE-SZ cohort[END_REF][START_REF] Whiteford | Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010[END_REF][START_REF] Desalegn | Quality of life and its association with psychiatric symptoms and socio-demographic characteristics among people with schizophrenia: A hospital-based cross-sectional study[END_REF][START_REF] Pinho | Affectivity in schizophrenia: Its relations with functioning, quality of life, and social support satisfaction[END_REF]. While no systematic review has synthetized data on quality of life in schizophrenia (SZ) so far, SZ remains the psychiatric disorder with the highest loss of quality-adjusted life years (QALYs) [START_REF] Karow | Better care for less money: cost-effectiveness of integrated care in multi-episode patients with severe psychosis[END_REF].

Identifying new factors associated with impaired quality of life (QoL) in schizophrenia (SZ) is a priority [START_REF] Andrianarisoa | Childhood trauma, depression and negative symptoms are independently associated with impaired quality of life in schizophrenia. Results from the national FACE-SZ cohort[END_REF] and is now possible by assessing a large sample of our national FACE-SZ cohort.

Major depression has been already identified as the most important feature for impaired SZ QoL [START_REF] Andrianarisoa | Childhood trauma, depression and negative symptoms are independently associated with impaired quality of life in schizophrenia. Results from the national FACE-SZ cohort[END_REF][START_REF] Alessandrini | A structural equation modelling approach to explore the determinants of quality of life in schizophrenia[END_REF]. Yet we don't know so far if this association is independent of sleep and hostility that are symptoms of major depression and frequent in SZ patients.

Sleep was associated with impaired QoL in an exploratory Israeli study published in 2004 independently of depression in 145 SZ patients [START_REF] Ritsner | Perceived quality of life in schizophrenia: relationships to sleep quality[END_REF]. A Portuguese study published in 2013 reported among 811 SZ patients, impaired sleep being associated with lower life satisfaction [START_REF] Brissos | Satisfaction with Life of Schizophrenia Outpatients and Their Caregivers: Differences between Patients with and without Self-Reported Sleep Complaints[END_REF]. A Chinese study carried out in 623 SZ outpatients found an association of sleep and mental QoL (assessed by the SF-12 scale) but not physical QoL in SZ patients [START_REF] Hou | Prevalence of Insomnia and Clinical and Quality of Life Correlates in Chinese Patients With Schizophrenia Treated in Primary Care[END_REF]. These results were replicated in a recent Spanish study [START_REF] Batalla-Martín | Insomnia in Schizophrenia Patients: Prevalence and Quality of Life[END_REF]. Yet these four studies reported limitations due to sample sizes or no adjustment for potential confounding factors including age, sex and illness characteristics. A standardized sleep evaluation has been implemented in the FACE-SZ cohort in 2015 [START_REF] Schürhoff | The 10year findings from the FondaMental Academic Center of Expertise for Schizophrenia (FACE-SZ): Review and recommendations for clinical practice[END_REF], which is a timely opportunity to address this issue.

Hostility may be the second culprit for impaired QoL in SZ. Hostility is a core dysfunction that may explain persecutory delusions and impaired functioning in schizophrenia [START_REF] Buck | Revisiting the validity of measures of social cognitive bias in schizophrenia: Additional results from the Social Cognition Psychometric Evaluation (SCOPE) study[END_REF]. Hostility has been associated with impaired QoL in FACE-SZ patients independently of positive and negative symptoms [START_REF] Ritsner | Predicting 10-year quality-of-life outcomes of patients with schizophrenia and schizoaffective disorders[END_REF][START_REF] Priebe | Association between symptoms and quality of life in patients with schizophrenia: a pooled analysis of changes over time[END_REF][START_REF] Jung | Clinician-rated functioning and patient-rated quality of life in schizophrenia: implications of their correspondence for psychopathology and side effects[END_REF], and more specifically with impaired friends' relationships [START_REF] Giacco | Friends and symptom dimensions in patients with psychosis: a pooled analysis[END_REF]. These findings were reinforced by targeting hostility showing effectiveness in improving life satisfaction but only in non-remitted SZ patients [START_REF] Gardsjord | Is going into stable symptomatic remission associated with a more positive development of life satisfaction? A 10-year follow-up study of first episode psychosis[END_REF]. Yet hostility was mostly explored as a clinician-rated single symptom with no dedicated scale, which is a limit of these results.

Major depression was also found to be associated with high weight gain risk [START_REF] Godin | Predictors of rapid high weight gain in schizophrenia: Longitudinal analysis of the French FACE-SZ cohort[END_REF] and weight gain has been associated with impaired QoL in schizophrenia [START_REF] Kolotkin | Impact of obesity on health-related quality of life in schizophrenia and bipolar disorder[END_REF][START_REF] Guo | The relationship between obesity and health-related quality of life in Chinese patients with schizophrenia[END_REF].

In summary, preliminary data suggested to explore sleep, hostility, and weight in addition to depression to identify new targets to improve SZ QoL. The bottleneck was the lack of large-scale standardized data so far but is now possible thanks to our FACE-SZ cohort. The objective was thus to determine if sleep quality, hostility, major depression and weight were independently associated with impaired QoL impairment in stabilized SZ outpatients and to determine which QoL area may be specifically concerned.

Population and methods

Study design, study population, diagnosis, ethical concerns

The FACE-SZ cohort has been described in previous articles [START_REF] Schürhoff | The 10year findings from the FondaMental Academic Center of Expertise for Schizophrenia (FACE-SZ): Review and recommendations for clinical practice[END_REF][START_REF] Schürhoff | A National network of schizophrenia expert centres: An innovative tool to bridge the research-practice gap[END_REF]. The FACE-SZ (FondaMental Academic Centers of Expertise for Schizophrenia) cohort is based on a French national network of 10 Schizophrenia Expert Centers (Bordeaux, Clermont-Ferrand, Colombes, Créteil, Grenoble, Lyon, Marseille, Montpellier, Strasbourg, Versailles), set up by a scientific cooperation foundation in France, the FondaMental Foundation (www.fondation-fondamental.org) and pioneered by the French Ministry of Research in order to create a platform that links thorough and systematic assessment to research [START_REF] Schürhoff | A National network of schizophrenia expert centres: An innovative tool to bridge the research-practice gap[END_REF].

Study population

Inclusion criteria

Consecutive clinically stable patients (defined by no hospitalization and no treatment changes during the 8 weeks before evaluation) with a DSM-IV-TR diagnosis of schizophrenia or schizoaffective disorder were consecutively included in the study. Diagnosis was confirmed by two trained psychiatrists of the Schizophrenia Expert Centres network. All patients were referred by their general practitioner or psychiatrist who subsequently received a detailed evaluation report with suggestions for personalized interventions.

Exclusion criteria

All patients with other diagnoses than schizophrenia (except for major depression, anxiety disorder, eating disorder and addictions) and those not speaking French were excluded.

Diagnosis

Patients were interviewed by members of the specialized multidisciplinary team of the Expert Center. Diagnoses interviews were carried out by two independent psychiatrists according to the Structured Clinical Interview for Mental Disorders (SCID 1.0) module B to H (Psychotic and associated symptoms, psychotic disorders, mood disorders, substance use disorders, anxiety disorders, somatoform disorders and eating disorders).

Ethical concerns

The study was carried out in accordance with ethical principles for medical research involving humans (WMA, Declaration of Helsinki). The assessment protocol was approved by the relevant ethical review board (CPP-Ile de France IX, January 18th, 2010). All data were collected anonymously. As this study include data coming from regular care assessments, a non-opposition form was signed by all participants.

Collected data

All scales were used in their French version. The psychometric properties and the rationale for the choice of the scales are described in [START_REF] Schürhoff | A National network of schizophrenia expert centres: An innovative tool to bridge the research-practice gap[END_REF].

QoL was assessed using the SQoL-18 questionnaire, a self-administered, multidimensional instrument developed and validated for the specific assessment of QoL in SZ patients [START_REF] Auquier | Development and validation of a patient-based health-related quality of life questionnaire in schizophrenia: the S-QoL[END_REF][START_REF] Boyer | The development of the S-QoL 18: a shortened quality of life questionnaire for patients with schizophrenia[END_REF] with 18 items describing eight dimensions: Psychological Well-being, Self-Esteem, Family Relationships, Friends' relationships, Resilience, Physical Well-being, Autonomy, and Sentimental Life, as well as a total score. Dimensions and total scores range from 0, indicating the lowest QoL, to 100, indicating the highest QoL. Internal consistency was satisfactory (item-internal consistency greater than 0.40; Cronbach's alpha coefficients ranged from 0.72 to 0.84). The scalability was satisfactory, with INFIT statistics within an acceptable range [START_REF] Boyer | The development of the S-QoL 18: a shortened quality of life questionnaire for patients with schizophrenia[END_REF].

Confounding variables

Sociodemographic and clinical characteristics (age, sex, education level, age at illness onset) were reported. Education level was a continuous variable (number of years of scholarship from primary school).

Variables hypothetically influencing QoL

Major depression was assessed with the Positive and Negative Syndrome Scale for Schizophrenia depressive factor [START_REF] Wallwork | Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia[END_REF]. The internal consistency of this fivefactor structure was good (Cronbach's alpha >0.70) in the relapse and chronic patients [START_REF] Lançon | Stability of the five-factor structure of the Positive and Negative Syndrome Scale (PANSS)[END_REF].No threshold has been determined so far [START_REF] Wallwork | Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia[END_REF][START_REF] Lançon | Stability of the five-factor structure of the Positive and Negative Syndrome Scale (PANSS)[END_REF].

Daily functioning and current illness severity were assessed with the Global Assessment of Functioning scale (GAF) [START_REF] Startup | The concurrent validity of the Global Assessment of Functioning (GAF)[END_REF].

The PANSS total score was not included as too collinear with the PANSS depressed factor. Positive and negative symptoms were proxy by the GAF score, which includes symptoms severity.

Sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI) [START_REF] Buysse | The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research[END_REF][START_REF] Blais | Evaluation of insomnia: validity of 3 questionnaires[END_REF]. This 19-item self-questionnaire generated a total score ranging from 0 to 21. We used the validated French version [START_REF] Blais | Evaluation of insomnia: validity of 3 questionnaires[END_REF]. A total score equal or above 5 is in favor of sleep disturbances with clinical significance. The PSQI has not been validated in SZ patients but was used in most of previous studies exploring sleep disturbances in SZ [START_REF] Waite | Treating Sleep Problems in Patients with Schizophrenia[END_REF][START_REF] Fang | Associations between sleep quality and inflammatory markers in patients with schizophrenia[END_REF][START_REF] Cosgrave | The interaction between subclinical psychotic experiences, insomnia and objective measures of sleep[END_REF][START_REF] Reeve | Sleep Disorders in Early Psychosis: Incidence, Severity, and Association With Clinical Symptoms[END_REF] and has been validated in other psychiatric disorders [START_REF] Ait-Aoudia | Validation of the French version of the Pittsburgh Sleep Quality Index Addendum for posttraumatic stress disorder[END_REF][START_REF] Perney | Measuring sleep disturbances in patients with alcohol use disorders: a short questionnaire suitable for routine practice[END_REF]. The PSQI demonstrated adequate internal consistency in post-traumatic disorder with Chronbach's α=0.72 [START_REF] Ait-Aoudia | Validation of the French version of the Pittsburgh Sleep Quality Index Addendum for posttraumatic stress disorder[END_REF].

Hostility was measured by the Buss-Perry Aggression Questionnaire (BPAQ) hostility score. While it has not been specifically validated in schizophrenia, BPAQ is a widely used self-rated measure showing internal consistency and stability over time [START_REF] Diamond | Factor Structure of the Buss-Perry Aggression Questionnaire (BPAQ) With Mentally Ill Male Prisoners[END_REF]. Retest reliability for the BPAQ over 9 weeks was satisfactory [START_REF] Buss | The Aggression Questionnaire[END_REF]. The BPAQ hostility demonstrated adequate internal consistency in post-traumatic disorder with Chronbach's α=0.77 [START_REF] Buss | The Aggression Questionnaire[END_REF].

Insight was measured by the Birchwood Insight Scale score, a brief selfreported measure with Chronbach's α=0.75 [START_REF] Birchwood | A selfreport Insight Scale for psychosis: reliability, validity and sensitivity to change[END_REF][START_REF] Cleary | Measuring insight through patient self-report: an in-depth analysis of the factor structure of the Birchwood Insight Scale[END_REF]. Current daily tobacco smoking was self-reported. Alcohol use disorder (the presence of at least 2 symptoms among the 11 explored in DSM-5 indicates an Alcohol Use Disorder) was evaluated with the Structured Clinical Interview for Mental Disorders (SCID 1.0) (module E substance use disorders) [START_REF] First | Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version[END_REF].

Body mass index (BMI) calculated as weight in kilograms divided by the square of the height in meters.

Treatments were reported. The antipsychotic treatments were classified according to their Anatomical-Therapeutic-Clinical ATC class. First-generation antipsychotics (FGA) were defined by ATC class N05AA to AC (phenothiazines),

NO5AD

(butyrophenones), NO5AF (thioxanthenes). Second-generation antipsychotics (SGA) were defined by ATC class N05AH (diazepines, oxazepines, thiazepines and oxepines) and NO5AL (benzamides) [START_REF] Misdrahi | Prevalence of and Risk Factors for Extrapyramidal Side Effects of Antipsychotics: Results From the National FACE-SZ Cohort[END_REF].

Statistical analyses

The aim was to explore the association of QoL with the following variables Then multivariate analyses using multiple linear regression were performed to determine QoL-associated variables selected from the previous univariate S-QoL 18 total score analysis based on a threshold p-value≤0.20. As classical significance levels, such as 0.05, can fail to identify important variables, we chose a p-value cutoff point of 0.2 for the selection process of variables in a multivariate model [START_REF] Bendel | Comparison of stopping rules in forward "stepwise" regression[END_REF][START_REF] Bursac | Purposeful selection of variables in logistic regression[END_REF][START_REF] Mickey | The impact of confounder selection criteria on effect estimation[END_REF].The S-QoL 18 total score and each of its dimensions were considered as separate dependent variables. Tobacco smoking was forced because of being reported in more than an half of stabilized outpatients and its association with a wide range of poor health outcomes [START_REF] Godin | Predictors of rapid high weight gain in schizophrenia: Longitudinal analysis of the French FACE-SZ cohort[END_REF][START_REF] Mallet | Tobacco smoking is associated with antipsychotic medication, physical aggressiveness, and alcohol use disorder in schizophrenia: results from the FACE-SZ national cohort[END_REF].

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The final models incorporated the standardized ß coefficients, which represent a change in the standard deviation of the dependent variable (QoL) resulting from a change of one standard deviation in the various independent variables. The independent variables with the higher standardized beta coefficients are those with a greater relative effect on QoL. The statistical significance level was set at p<0.05 for a two-sided test, except for the multivariate analysis (p≤0.01) to reduce the chance of false positive. Data were analyzed using SPSS 17.0 software (SPSS Inc., Chicago, IL).

Results

Overall, 559 patients (mean age=31+/-9 years, 74% male sex) have been consecutively included in the FACE-SZ cohort. Sample characteristics are presented in Table 1, univariate analyses in Table 2.

In multivariate analyses (Table 3), impaired QoL has been significantly associated with respectively impaired sleep quality, increased hostility, major depression, impaired functioning and impaired insight independently of age, sex, treatments, tobacco smoking and body mass index. More specifically, impaired sleep quality has been associated with impaired psychological and physical well-being.

Hostility has been associated with impaired psychological well-being and self-esteem, impaired friends' relationships and impaired autonomy. Major depression was associated with impaired psychological and physical well-being and impaired selfesteem. Body mass index was associated with impaired physical well-being. Tobacco smoking was associated with higher level of friends' relationships.

Discussion

The analysis of the FACE-SZ enabled us to identify sleep, hostility, depression and body mass index as independent factors associated with impaired QoL in SZ. Future studies should determine if improving these factors may improve QoL in SZ.

Sentimental life is the most impaired area of SZ QoL, yet no intervention to date aim at helping SZ patients to recover a satisfying sentimental life. We have recently identified sexual dysfunctions in >40% of stabilized SZ outpatients [START_REF] Fond | Sexual dysfunctions are associated with major depression, chronic inflammation and anticholinergic consumption in the real-world schizophrenia FACE-SZ national cohort[END_REF][START_REF] Dumontaud | Sexual dysfunctions in schizophrenia: Beyond antipsychotics. A systematic review[END_REF].

Future studies should determine the role of sexual dysfunctions in SZ sentimental life.

Depression was associated with impaired QoL in FACE-SZ independently of sleep and hostility. This confirms our previous findings in FACE-SZ [START_REF] Andrianarisoa | Childhood trauma, depression and negative symptoms are independently associated with impaired quality of life in schizophrenia. Results from the national FACE-SZ cohort[END_REF], yet we analyzed depression in a quantitative manner in the present analyses and with PANSS depressive factor instead of Calgary Depression Rating Scale (with a cut-off of 6 defining major depression). This suggests that even low/residual depression may be associated with impaired QoL. Depression is frequent and undertreated in SZ 38 .

Depression has been associated with impaired physical well being in our results, which may be mediated by physical pain previously identified in one of five FACE-SZ patients [START_REF] Fond | Selfreported pain in patients with schizophrenia. Results from the national first-step FACE-SZ cohort[END_REF].

We confirmed that sleep was associated with a wide range of impaired psychological and physical well being, consistently with previous studies [START_REF] Ritsner | Perceived quality of life in schizophrenia: relationships to sleep quality[END_REF][START_REF] Brissos | Satisfaction with Life of Schizophrenia Outpatients and Their Caregivers: Differences between Patients with and without Self-Reported Sleep Complaints[END_REF][START_REF] Kaskie | Schizophrenia and sleep disorders: links, risks, and management challenges[END_REF][START_REF] Xiang | Prevalence and correlates of insomnia and its impact on quality of life in Chinese schizophrenia patients[END_REF]. As mentioned in the rationale, the association between impaired sleep and well being was well documented in non-SZ populations [START_REF] Perach | The psychological wellbeing outcomes of nonpharmacological interventions for older persons with insomnia symptoms: A systematic review and meta-analysis[END_REF] but in SZ we still don't know the respective association of sleep and depression with QoL To exceed this limit, our results were adjusted for depression [START_REF] Cosgrave | The interaction between subclinical psychotic experiences, insomnia and objective measures of sleep[END_REF]. Future studies should determine if improving sleep may improve QoL in SZ patients. Strategies improving sleep in SZ may be divided in two types: (1) Among pharmacological approaches, some sedative antipsychotics may improve sleep through antihistaminic action [START_REF] Meng | Effects of chlorpromazine on sleep quality, clinical and emotional measures among patients with schizophrenia[END_REF],

yet they also increase diurnal sedation and diminish physical activity, inducing weight gain. Weight gain may impact physical well-being, which may lead to a vicious circle [START_REF] Sturludóttir | The effects of physical activity intervention on symptoms in schizophrenia, mental well-being and body composition in young adults[END_REF]. Hypnotics are addictive and not recommended in the long-term [START_REF] Bourcier | A systematic review of regulatory and educational interventions to reduce the burden associated with the prescriptions of sedative-hypnotics in adults treated for sleep disorders[END_REF]. Future studies should determine if pharmacological approaches may improve sleep with a good benefit/risk ratio in SZ. (2) Among non-pharmacological approaches, psychoeducation, third-wave behavioral and cognitive therapies, decreased screen exposure before sleep, diurnal physical activity, tobacco/cannabis cessation and alcohol reduction remain insufficiently developed in SZ patients despite their potential efficacy to improve SZ QoL [START_REF] Desalegn | Quality of life and its association with psychiatric symptoms and socio-demographic characteristics among people with schizophrenia: A hospital-based cross-sectional study[END_REF][START_REF] Alessandrini | A structural equation modelling approach to explore the determinants of quality of life in schizophrenia[END_REF][START_REF] Batalla-Martín | Insomnia in Schizophrenia Patients: Prevalence and Quality of Life[END_REF].

Hostility was associated with a wide range of impaired QoL domains in FACE-SZ (including relationships with friends and sentimental life, impaired selfesteem and psychological well being and impaired autonomy) consistently with previous studies [START_REF] Ritsner | Predicting 10-year quality-of-life outcomes of patients with schizophrenia and schizoaffective disorders[END_REF][START_REF] Priebe | Association between symptoms and quality of life in patients with schizophrenia: a pooled analysis of changes over time[END_REF][START_REF] Jung | Clinician-rated functioning and patient-rated quality of life in schizophrenia: implications of their correspondence for psychopathology and side effects[END_REF][START_REF] Giacco | Friends and symptom dimensions in patients with psychosis: a pooled analysis[END_REF][START_REF] Gardsjord | Is going into stable symptomatic remission associated with a more positive development of life satisfaction? A 10-year follow-up study of first episode psychosis[END_REF]. Interventions targeting hostility may be also divided in pharmacological and non-pharmacological interventions. (1) Among pharmacological approaches, the following interventions have been classified in order of evidence for efficacy: paliperidone-extended release, clozapine, propranolol, valproate and famotidine [START_REF] Victoroff | Pharmacological management of persistent hostility and aggression in persons with schizophrenia spectrum disorders: a systematic review[END_REF]. Benzodiazepine cessation may also improve hostility [START_REF] Fond | Medication and aggressiveness in real-world schizophrenia. Results from the FACE-SZ dataset[END_REF] (2). Among non-pharmacological strategies, cognitive and behavioral therapies have shown efficacy [START_REF] Dubreucq | Towards an improved access to psychiatric rehabilitation: availability and effectiveness at 1-year follow-up of psychoeducation, cognitive remediation therapy, cognitive behaviour therapy and social skills training in the FondaMental Advanced Centers of Expertise-Schizophrenia (FACE-SZ) national cohort[END_REF]. The evidence for family intervention remains insufficient in this domain [START_REF] Okpokoro | Family intervention (brief) for schizophrenia[END_REF]. As for sleep, future studies should confirm if improving hostility may improve SZ QoL Body mass index was also associated with impaired physical well being in our results independently of depression and treatments. This association was shown for the first time due to lack of previous explorations on this issue in schizophrenia.

Combined with above-mentioned results, body-orientated therapies showing effectiveness in non-SZ populations (e.g. weight loss, nutrition, physical activity, yoga [START_REF] Ravindran | Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 5. Complementary and Alternative Medicine Treatments[END_REF][START_REF] Holt | Structured lifestyle education to support weight loss for people with schizophrenia, schizoaffective disorder and first episode psychosis: the STEPWISE RCT[END_REF][START_REF] Stiekema | Effects of a lifestyle intervention on psychosocial well-being of severe mentally ill residential patients: ELIPS, a cluster randomized controlled pragmatic trial[END_REF]) appear of peculiar interest in SZ patients with impaired physical well being and should be further tested.

Current daily tobacco smoking was associated with better friends relationships, which may indicate the prosocial effect of smoking (sharing smoking activity with others) and may also explain the difficulties for quitting smoking [START_REF] Underner | Stopping and reducing smoking in patients with schizophrenia[END_REF].

These issues should be addressed by specific interventions programs addressing the need for prosocial strategies for isolated SZ patients.

Limits and perspectives. Due to the cross-sectional design of the study, no causal relationship can be inferred from the results. The PSQI and Buss&Perry scale should be validated in schizophrenia in future studies. Neuroticism, physical activity, internalized stigma and stigma resistance have not been explored in FACE-SZ to avoid the patients' assessment overburden while they have been associated with impaired QoL in SZ [START_REF] Ridgewell | Personality traits predicting quality of life and overall functioning in schizophrenia[END_REF][START_REF] Sibitz | Stigma resistance in patients with schizophrenia[END_REF][START_REF] Sibitz | The impact of the social network, stigma and empowerment on the quality of life in patients with schizophrenia[END_REF]. Genetic variations have been identified in sleep disorders in SZ patients and should be further explored [START_REF] Assimakopoulos | Genetic Variations Associated with Sleep Disorders in Patients with Schizophrenia: A Systematic Review[END_REF].

Strengths. The multivariate models enabled us to determine four independent factors for improving Qol in SZ: sleep, hostility, depression and body mass index.

Multiple confounding factors were explored and the significant level was set at 0.01 to avoid type 1 error. Each dimension was assessed with dedicated standardized scales, especially PSQI for sleep and Buss&Perry for hostility, which strengthens the quality of these results. The use of structured interviews for alcohol disorders diagnoses may be mentioned as another strength.

Conclusion

Analyzing FACE-SZ has revealed that sleep, hostility, depression and body mass index may be targeted to improve quality of life (including psychological and physical well being) in SZ patients. These four targets remain therapeutic challenges for clinicians, patients and families to date with no available guidelines and insufficient therapeutic intervention evaluations. Developing effective programs is urgently needed to improve their effectiveness and thus the QoL of SZ patients. * Quality of life: Scores range from 0 to 100; higher scores represent higher QoL.

Table 1 .

 1 Sample characteristics (N=559).

	N (%) or Mean (SD)

Acknowledgments and funding source

Other members of the FACE-SZ group: Blanc O, Msc; Chereau-Boudet I a , MD;

Coulon N a,e , MD PhD; Denizot H a , MD; Dorey JMa,g, MD; Laouamri H a , Msc. a Fondation Fondamental This work was funded by AP-HM (Assistance Publique des Hôpitaux de Marseille), Fondation FondaMental (RTRS Santé Mentale), by the Investissements d'Avenir program managed by the ANR under reference ANR-11-IDEX-0004-02 and ANR-10-COHO-10-01, and by INSERM (Institut National de la Santé et de la Recherche Médicale).

We express all our thanks to the nurses, and to the patients who were included in the present study. We thank Hakim Laouamri, and his team (Stéphane Beaufort, Seif Ben Salem, Karmène Souyris, Victor Barteau and Mohamed Laaidi) for the development of the FACE-SZ computer interface, data management, quality control and regulatory aspects. We thank George Anderson for editorial assistance.

Conflicts of interest

None declared.

Contributors

GF and LB performed the statistical analysis. GF and LB wrote the first complete manuscript. All authors were involved in the patients' recruitment, the clinical evaluation, acquisition of the clinical data, modified the manuscript and approved the final version. S-QoL 18 : Scores range from 0 to 100; higher scores represent higher QoL. PANSS total score and other subscores were not included in the analyses due to collinearity with PANSS depressed factor. Current illness severity was proxy by the GAF scores which includes both positive/negative symptoms and functioning ß: standardized beta coefficient (ß represents the change of the standard deviation in QoL score resulting from a change of one standard deviation in the independent variable) * p≤0.05. ** p≤0.01.