ANXIETY AND PANIC ATTACKS

Biological factors, such as genetic background, neurotransmitter and neuroendocrine systems, social factors, and psychological factors, such as, personality traits and ego defense mechanisms, contribute to the pathogenesis of anxiety. Τοwards explaining anxiety, a number of neurone's systems, neuroanatomical regions and various hormonic levels of mulfunction have been suggested.

The GABA-nergic hypothesis is based on the finding that the benzodiazepines increase the function of GABA-A receptor, allowing the inflow of chloric anions into the cell.

The noradrenergic hypothesis is based on the findings of an abnormal activity of locus cerulus and a presynaptic downregulation of norepinephrine neurons.

The serotonergic theory is based on the assumption that there is hypersensitivity of the 5-HT receptor. From neuroanatomical point of view, it seems that anxiety or panic attacks begin with stimulation of irritable foci in one of three brainstem areas: the medulary chemoreceptors, the noradrenergic pontine locus cerulus or the serotogenic midbrain dorsal raphe. The limbic lobe is believed to be the center of anticipatory anxiety and the prefrontal cortex the region of phobic avoidance. Also, there is convincing evidence that the serotonergic projections inhibit dopamine function in the striatum and cortex inhibiting the synaptic release of dopamine and probably the synthesis of dopamine. The serotonergic receptors are grouped on the basis of shared genetic sequences and second messenger systems in four groups : 1. The 5HT-1 family ( 5HT-1A, 5HT-1D, 5HT-1E and 5HT- 1F ) which uses G-protein - mediated signal transduction. 2. The 5HT-2 family ( 5HT-2A, 5HT-2B, 5HT- 2C , 5HT-4, 5HT-6, 5HT-7 ) which uses phosphoinositol - mediated signal transduction. 3. The 5HT-3 receptor which uses ion - gated channels and 4. The 5HT-5 family , a new group of 5HT receptors, which contains the 5HT-5A and 5HT-5B receptors.

Abnormalities of both 5HT neurotransmission and HPA axis activity are found in anxiety, but abnormal 5HT neurotransmission seems to be the key factor. Serotonin has also implicated in the pathogenesis of depressive and obsessive-compulsive symptoms which are common features in anxiety disorders. Recent studies suggest that the CRH systems and the locus cerulus-norepinephrine system create a bronchus of positive feedback, that results in a number of clinical and biochemical manifestations of anxiety attacks.

There is a solid pharmacological basis for the observed clinical advantages of most antidepressants. They can be considered as serotonin (5-HT) reuptake inhibitor with potent antidepressant and anxiolytic activity, acting via serotonin binding on the serotonin transporter.

CYP450 Isozyme Inhibition Profiles

DEPRESSION

Κλινική εικόνα Κατάθλιψης

Τα άτομα που παραπονούνται για κατάθλιψη συχνά αναφέρονται σε μια επίμονη αίσθηση κατάπτωσης ή θλίψης, ή έλλειψη ενδιαφέροντος ή ικανοποίησης (ανηδονία). Εντούτοις, πολλά άτομα με κατάθλιψη δεν αναγνωρίζουν στον εαυτό τους την κατάθλιψη. Αυτό συμβαίνει ιδιαίτερα στα άτομα με νοητική υστέρηση, στα παιδιά, στους εφήβους και στο γηριατρικό πληθυσμό. Τα άτομα αυτά είτε παρουσιάζουν οξυθυμία είτε αναφέρεται από άλλους ότι βρίσκονται σε κατάθλιψη ή ότι έχουν χάσει το ενδιαφέρον τους για ζωή γιατί είναι συχνά δακρυσμένα η λυπημένα ή Δε συμμετέχουν σε δραστηριότητες που, υπό άλλες συνθήκες θα τους προκαλούσαν ευχαρίστηση. Υπάρχουν, όμως, κι άλλα συμπτώματα που συχνά συνοδεύουν την καταθλιπτική διάθεση ή την ανηδονία, που μάλιστα μπορεί να αναφερθούν από τον ασθενή στην πρώτη συνέντευξη. Οι διαταραχές του ύπνου και της ΄όρεξης, τα οποία εμφανίζονται είτε σε ελάχιστο είτε σε υπερβολικό βαθμό, είναι συνηθισμένες. Αλλαγή του βάρους κατά τουλάχιστον 5% μέσα σε ένα μήνα, μπορεί επίσης να συνοδεύει τέτοια συμπτώματα. Οι ασθενείς με κλινικά διαγνωσμένη κατάθλιψη μπορεί επίσης να παραπονεθούν για σχεδόν καθημερινή έλλειψη ενεργητικότητας ή κόπωση, μείωση της ικανότητας συγκέντρωσης και μειωμένη ικανότητα λήψης αποφάσεων. Οι ασθενείς μπορεί να βρίσκονται σε ένταση ή αναστάτωση, ή αντίθετα να έχουν επιβραδυμένη κινητικότητα. Πολλοί έχουν μειωμένη αυτοεκτίμηση ή νιώθουν υπερβολικές ενοχές και τείνουν να ανακυκλώνουν τα πράγματα: δεν πρόκειται για μια απλή επιτίμηση του εαυτού τους. Επιπλέον, ασθενείς με συνοσηρότητα που παίρνουν παράλληλες φαρμακευτικές αγωγές μπορεί επίσης να εμφανίσουν συμπτώματα παρόμοια με αυτά της κατάθλιψης. (π.χ. αϋπνία, χάσιμο βάρους, κόπωση), πράγμα που περιπλέκει την κατάσταση.

Είναι πολύ σημαντικό ότι ο κλινικός πρέπει να καταλήξει αν ο ασθενής έχει όντως επαναλαμβανόμενες σκέψεις θανάτου (και όχι μόνο φόβο του θανάτου), αν έχει παθητικό αυτοκτονικό ιδεασμό (δηλαδή σκέψεις αυτοκτονίας χωρίς συγκεκριμένο σχέδιο, ή αν προτιμά να είχε πεθάνει παρά να είναι ζωντανός), ή αν ο ασθενής έχει ενεργό αυτοκτονικό ιδεασμό (δηλαδή συγκεκριμένο σχέδιο αυτοκτονίας ή απόπειρα στο παρελθόν). Η πιο επικίνδυνη στιγμή για τους αυτοκτονικούς ασθενείς είναι όταν αρχίζουν να αισθάνονται περισσότερο ενεργητικοί αλλά εξακολουθούν να έχουν σκέψεις αυτοκτονίας. Η περίοδος αυτή είναι διανύεται συχνότατα κατά την αρχική θεραπεία και αμέσως μετά το εξιτήριο για όσους ασθενείς έχουν νοσηλευτεί. Το 50% περίπου των ατόμων που αυτοκτονούν έχουν πρότερη διάγνωση κατάθλιψης. Πρώιμοι παράγοντες που αυξάνουν την επικινδυνότητα στους καταθλιπτικούς ασθενείς είναι οι κρίσεις πανικού, ψυχικό άγχος, ανηδονία, χρήση ουσιών και επίμονη αϋπνία. Οι μακροπρόθεσμοι παράγοντες επικινδυνότητας περιλαμβάνουν την απελπισία, τον αυτοκτονικό ιδεασμό και την ύπαρξη προηγούμενων αποπειρών.

Η μείζων καταθλιπτική διαταραχή, προσβάλλει ένα μεγάλο ποσοστό του πληθυσμού. Ο δια βίου επιπολασμός κυμαίνεται από 10% έως 25% στις γυναίκες και από 5% έως 12% στους άντρες. Αυτά τα ποσοστά είναι ανεξάρτητα από την εθνικότητα, τη μόρφωση, το εισόδημα και την οικογενειακή κατάσταση. Η μείζων κατάθλιψη έχει υψηλό δείκτη θνησιμότητας: μέχρι και 15 % των ασθενών αυτοκτονούν. Η μείζων κατάθλιψη μπορεί να ξεκινήσει σε οποιαδήποτε ηλικία, αλλά η μέση ηλικία έναρξης είναι περίπου τα 25 έτη. Η πορεία της υποτροπιάζουσας μείζονος κατάθλιψης ποικίλλει. Κάποιοι ασθενείς έχουν μεμονωμένα επεισόδια μεταξύ των οποίων μεσολαβούν πολλά χρόνια, άλλοι βιώνουν ομάδες επεισοδίων και άλλοι έχουν ένα προοδευτικά αυξανόμενο αριθμό επεισοδίων, μεγαλώνοντας. Περίπου οι μισοί από τους ασθενείς με ένα μείζων καταθλιπτικό επεισόδιο έχουν και ένα δεύτερο. Τα άτομα που έχουν δύο επεισόδια έχουν 70% πιθανότητα να έχουν και τρίτο. Επιπλέον, 5% έως 10% των ασθενών με μείζον καταθλιπτικό επεισόδιο στην πορεία εμφανίζουν μανιακό επεισόδιο (π.χ. διπολική ή μανιοκαταθλιπτική διαταραχή). Τα συμπτώματα του μείζονος καταθλιπτικού επεισοδίου μπορούν να αναπτυχθούν μέσα σε μέρες η εβδομάδες, ενώ τα πρόδρομα συμπτώματα όπως το άγχος και τα ήπια καταθλιπτικά συμπτώματα μπορεί να διαρκέσουν εβδομάδες ή και μήνες. Ένα επεισόδιο που δεν έχει αντιμετωπιστεί συνήθως διαρκεί τουλάχιστον έξι μήνες ανεξάρτητα με την ηλικία έναρξης. Οι περισσότεροι ασθενείς παρουσιάζουν πλήρη ύφεση. Στο 20 έως 30% των περιπτώσεων η ύφεση είναι μόνο μερική και στο 5% έως 10% το μείζον καταθλιπτικό επεισόδιο μπορεί να διαρκέσει για 2 ή περισσότερα χρόνια.

Φαρμακευτική θεραπεία κατάθλιψης

Βραχυχρόνιες ψυχοθεραπευτικές παρεμβάσεις, όπως η γνωσιακή και η διαπροσωπική θεραπεία, έχουν αποδειχθεί εξίσου αποτελεσματικές με τις φαρμακευτικές θεραπείες στις ήπιες μορφές κατάθλιψης. Όμως, οι πιο βαριές καταθλίψεις ανταποκρίνονται καλύτερα στη φαρμακοθεραπεία ή στην ηλεκτροσπασμοθεραπεία ( ECT ).

Το 60% έως 80% των ασθενών με μείζονα κατάθλιψη ανταποκρίνεται σε μία και μόνη φαρμακοθεραπεία, σε επαρκή δόση, διάρκειας τουλάχιστον 6 εβδομάδων. Από τους υπόλοιπους, οι περισσότεροι θα έχουν τουλάχιστον μια μερική ανταπόκριση. Το 10% -15% των ασθενών Δε βελτιώνονται επαρκώς. Για όσους δεν ανταποκρίνονται πλήρως στην πρώτη φαρμακευτική προσπάθεια ο συνδυασμός φαρμάκων ή η αλλαγή σε διαφορετικό φάρμακο είναι συχνά αποδοτική. Οι περισσότεροι ασθενείς που είναι ανθεκτικοί στη φαρμακευτική θεραπεία συχνά ανταποκρίνονται στο ECT . Πολλοί ασθενείς που θεωρούνται ανθιστάμενοι στη φαρμακευτική αγωγή, συχνά δεν την έχουν λάβει σε επαρκή δόση ή διάρκεια. Επίσης, ασθενείς με συνυπάρχουσες ψυχιατρικές διαταραχές, όπως διαταραχές προσωπικότητας ή ψυχωτικές διαταραχές έχουν χαμηλότερη συχνότητα ανταπόκρισης.

Οι περισσότεροι από τους ασθενείς που πάσχουν από μείζονα κατάθλιψη με ψυχωτικά στοιχεία ανταποκρίνονται καλύτερα στο ECT ή σε συνδυασμό ενός αντικαταθλιπτικού και ενός αντιψυχωτικού (70%-80%), από ότι αν αντιμετωπιστούν με ένα μόνο από αυτά (30%-50%). Η άτυπη κατάθλιψη (που χαρακτηρίζεται από αναστροφή των ζωτικών συμπτωμάτων όπως αυξημένος ύπνος και όρεξη, ευαισθησία στην απόρριψη και έντονο άγχος) ανταποκρίνεται καλύτερα στους αναστολείς της μονοαμινικής οξειδάσης (ΜΑΟΙ s ) ή στους εκλεκτικούς αναστολείς επαναπρόσληψης της σεροτονίνης ( SSRIs ) σε σχέση με τα τρικυκλικά αντικαταθλιπτικά ( TCAs ). Οι πιο βαριές καταθλίψεις σε νοσοκομειακούς ασθενείς τείνουν να ανταποκρίνονται καλύτερα στα τρικυκλικά ή σε ουσίες που επηρεάζουν τόσο τη σεροτονίνη όσο και τη νορεπινεφρίνη (π.χ βενλαφαξίνη [ Efexor ]), σε σχέση με τους SSRIs . Στους εξωνοσοκομειακούς ασθενείς καμία ομάδα αντικαταθλιπτικών δεν έχει δείξει κάποιο ιδιαίτερο πλεονέκτημα ως προς την αποτελεσματικότητα. Στον Πίνακα 3 παρατίθενται οι παράγοντες που αφορούν στην επιλογή του αντικαταθλιπτικού.

Τα περισσότερα από τα παλιά φάρμακα, όπως οι ΜΑΟΙ s και τα TCAs έχουν λιγότερο ευνοϊκό προφίλ παρενεργειών σε σχέση με τα νέα φάρμακα όπως τα SSRIs, τους αναστολείς επαναπρόσληψης σεροτονίνης – νορεπινεφρίνης ( SNRIs ), και τα άτυπα αντικαταθλιπτικά. Όμως, οι ΜΑΟΙ s και τα TCAs θα πρέπει να αρχίζουν σε χαμηλότερες δόσεις και να αυξάνονται σταδιακά μέχρι την τελική δόση. Από την άλλη πλευρά, πολλοί SSRIs και SNRIs μπορούν να αρχίσουν με την αποτελεσματική δόση. Για κάποια αντικαταθλιπτικά τα επίπεδα στο αίμα μπορούν να υπολογιστούν ώστε να ελεγχθεί η συμμόρφωση του ασθενή ή να εκτιμηθεί η τοξικότητα και οι παρενέργειες. Όμως, τα επίπεδα αίματος μόνο λίγων αντικαταθλιπτικών (π.χ. νορτριπτιλίνη [ Nortrilen ], ιμιπραμίνη [ Tofranil *] και δεσιπραμίνη [ Trittico ] ) σχετίζονται με τη θεραπευτική ανταπόκριση.

Τα αποτελέσματα των περισσότερων αντικαταθλιπτικών θεραπειών εξελίσσονται αργά μέσα σε αρκετές ημέρες ή εβδομάδες. Μία επαρκής θεραπεία θα περιλάμβανε την κατάλληλη δόση για τουλάχιστον 3-6 εβδομάδες. Εάν η ανταπόκριση είναι ανεπαρκής, μπορεί να είναι αποτελεσματική η αλλαγή σε ένα διαφορετικό αντικαταθλιπτικό (μετά από περίοδο διακοπής, αν είναι δυνατόν) ή η ενδυνάμωση του αντικαταθλιπτικού με κάποιον άλλο παράγοντα όπως έναν σταθεροποιητή του συναισθήματος (π.χ. λίθιο [ Milithin , Priadel , Lithiofor ]), μια θυροειδική ορμόνη (π.χ. λιοθυρονίνη [Τ3]), κάποιο άλλο αντικαταθλιπτικό (π.χ. συνδυασμός SSRI με αναστολέα επαναπρόσληψης νορεπινεφρίνης ή ντοπαμίνης) ή βουσπιρόνη ( Bespar ένας 5- HT 1 A αγωνιστής). Ασθενείς που παρόλα αυτά δεν ανταποκρίνονται θα πρέπει να επανεκτιμηθούν ως προς την αρχική διάγνωση ή την παρουσία συνοσηρότητας, η οποία θα μπορούσε να επιπλέξει την έκβαση της θεραπείας. Από τη στιγμή που ο ασθενής περιέλθει σε πλήρη ύφεση συνιστάται θεραπεία συντήρησης για τουλάχιστον 6 μήνες ώστε να μειωθεί η πιθανότητα υποτροπής. Όμως, λόγω της ιδιότητας της μείζονος κατάθλιψης να υποτροπιάζει, ενδείκνυται η προληπτική (μακροπρόθεσμη) θεραπεία ειδικότερα σε ασθενείς με περισσότερα από 2 προηγούμενα καταθλιπτικά επεισόδια. Επίσης, η θεραπεία συντήρησης με πλήρη δόση (π.χ. με την ίδια δόση που απαιτείται για να υφεθεί ένα οξύ επεισόδιο) παρατηρήθηκε ότι σε πολλές περιπτώσεις είναι αποτελεσματικότερη κατά της υποτροπής από θεραπείες με μικρότερη δόση.

Συνδυασμοί αντικαταθλιπτικών μπορεί να χρησιμοποιηθούν για την αντιμετώπιση της ανθιστάμενης κατάθλιψης. Συνήθως συνδυάζονται αντικαταθλιπτικά από 2 διαφορετικές ομάδες, ώστε να μεγιστοποιηθεί το αποτέλεσμα, στοχεύοντας σε διαφορετικά νευρομεταβιβαστικά συστήματα. Συνδυάζοντας 2 αντικαταθλιπτικά συνήθως αυξάνονται τα επίπεδα του ενός ή και των δύο, γεγονός που καθιστά αναγκαία την παρακολούθηση των επιπέδων, ιδιαίτερα μάλιστα εάν πρόκειται για TCAs όπου χρειάζεται να προλάβουμε ανεπιθύμητες και τοξικές επιδράσεις, όπως τις επιληπτικές κρίσεις. Αναφορές περιστατικών και ανοικτές δοκιμές έδειξαν ότι ο συνδυασμός ενός TCA, όπως δεσιπραμίνη (Norpramin*) ή νορτριπτιλίνης (Nortrilen) με έναν SSRI ή τη βουπροπιόνη ήταν αποτελεσματικός στην αντιμετώπιση ανθιστάμενης στη θεραπεία κατάθλιψης. Περισσότερες μελέτες χρειάζονται ώστε να ελεγχθεί η αποτελεσματικότητα των συνδυασμών και οι μακροχρόνιες συνέπειες. Συνδυασμοί ενός SSRI με βουπροπιόνη ή μιρταζαπίνη (Remeron) αναφέρθηκαν επίσης σαν ιδιαίτερα χρήσιμοι. Άλλοι συνδυασμοί με τα νεώτερα αντικαταθλιπτικά δεν έχουν ακόμη μελετηθεί.

Οι ηλικιωμένοι ασθενείς ανέχονται γενικά τις παρενέργειες των εκλεκτικών αναστολέων επαναπρόσληψης σεροτονίνης (SSRIs), των αναστολέων επαναπρόσληψης σεροτονίνη-νορεπινεφρίνη (SNRIs), και των άλλων άτυπων αντικαταθλιπτικών, πολύ καλύτερα από τις παρενέργειες των τρικυκλικών αντικαταθλιπτικών (TCAs) και των αναστολέων της μονοαμινοξειδάσης (MAOIs). Οι ασθενείς αυτοί τείνουν να είναι ιδιαίτερα ευαίσθητοι στις αντιχολινεργικές επιδράσεις, οι οποίες μπορεί να προκαλέσουν δυσκοιλιότητα, κατακράτηση ούρων, και ντελίριο και στις αδρενεργικές επιδράσεις, οι οποίες μπορεί να προκαλέσουν ορθοστατική υπόταση και συνεπώς πτώσεις στο έδαφος. Επιπρόσθετα, επειδή τα TCAs είναι τύπου 1Α αντιαρρυθμικά, αντενδείκνυνται σε ασθενείς με γνωστή καρδιακή νόσο επειδή θα διατρέχουν μεγαλύτερο κίνδυνο για ανάπτυξη προβλημάτων αγωγιμότητας. Επίσης, οι γηριατρικοί ασθενείς μπορεί να είναι γενικά περισσότερο ευαίσθητοι στις καρδιολογικές παρενέργειες από τη χρήση TCAs. Οι πλέον προβληματικές παρενέργειες των σεροτονεργικών φαρμάκων είναι η ευερεθιστότητα και η απώλεια βάρους. Τέλος, οι πιο βαριές καταθλίψεις με μελαγχολικά και ψυχωτικά στοιχεία δεν απαντούν τόσο καλά στα νεώτερα αντικαταθλιπτικά όπως απαντούν στα TCAs ή τα SNRIs. Στις περιπτώσεις αυτές, η ηλεκτροσπασμοθεραπεία με την κατάλληλη ιατρική υποστήριξη παραμένει μία ασφαλής και αποτελεσματική θεραπεία για τους ηλικιωμένους ασθενείς, ειδικότερα αυτούς με βαριά ψυχωτική κατάθλιψη. Οι δόσεις έναρξης στους γηριατρικούς ασθενείς είναι πολύ χαμηλότερες από ότι στους υγιείς νεώτερους. Επίσης, ο ρυθμός αύξησης της δόσης και το εύρος της θεραπευτικής δόσης είναι χαμηλότερος.

Οι μελέτες τερατογένεσης από τη χρήση αντικαταθλιπτικών κατά την εγκυμοσύνη είναι περιορισμένες. Επειδή υπάρχει μεγαλύτερη κλινική εμπειρία με τα TCAs, εάν ένας ασθενής χρειάζεται να λάβει αγωγή στη διάρκεια της εγκυμοσύνης, είναι καλύτερο να προτιμηθούν τα TCAs, έναντι των νεώτερων αντικαταθλιπτικών. Δεν βρέθηκε αυξημένος κίνδυνος για ανάπτυξη συγγενών διαμαρτιών μετά από χρήση TCAs κατά την εγκυμοσύνη. Έχουν αναφερθεί μεμονωμένα περιστατικά νεογνών με σημεία απόσυρσης μετά από χρήση TCAs στην περίοδο εγγύς του τοκετού. Τα συμπτώματα αυτά περιλαμβάνουν ευερεθιστότητα και εκνευρισμό. Μελέτες με χρήση φλουοξετίνης (Ladose) κατά το πρώτο τρίμηνο δεν έδειξαν κάποια σύνδεση με εμβρυϊκές διαμαρτίες. Ίσως η λήψη του φαρμάκου αυτού να συνδέεται με αυξημένο κίνδυνο περιγεννητικών επιπλοκών. Πρόσφατη μελέτη με τη φλουοξετίνη δεν έδειξε διαφορές στο IQ, τη γλωσσική ικανότητα και τη συμπεριφορά παιδιών που είχαν σαν έμβρυα εκτεθεί στο φάρμακο. Κάποιοι από τους νεώτερους SSRIs, όπως η φλουβοξαμίνη (Dumyrox), η παροξετίνη (Seroxat) και η σερταλίνη (Zoloft), χορηγούμενες στις συνιστώμενες δόσεις, δεν έδειξαν να αυξάνουν τον κίνδυνο τερατογένεσης. Δεν υπάρχουν μελέτες που να αφορούν τους MAOIs, τους SNRIs ή τα άλλα άτυπα αντικαταθλιπτικά.

ANOREXIA NERVOSA

1. CLINICAL AND ETIOLOGICAL ISSUES IN PATIENTS WITH ANOREXIA NERVOSA

1.1. HISTORY

Official history has it that the French psychiatrist Ernest-Charles Lasegue (1816-1833) and the English physician Sir William Withey Gull (1816-1890) simultaneously and independently presented descriptions of a new syndrome of eating disorders among adolescent women. Lasegue described his clinical and therapeutical experiences with eight female patients whose eating habits were severely disturbed in a paper which appeared in ‘Archives Generales de Medicine' in April 1873. Lasegue named this syndrome ‘Anorexie hysterique'. A month after Lasegue's paper appeared in English medical press, the British physician Sir William Gall gave a lecture at the Clinical Society in London . Accounts of this lecture by listeners were published shortly afterwards in 1873. When the lecture itself was published in 1874, its title introduced the term since conferred on the syndrome: ‘Anorexia Nervosa (Anorexia Hysterica, Apepsia Hysterica)' [1].

1.2. CLINICAL FEATURES

Anorexia Nervosa is characterized by a profound disturbance of body image and the relentless pursuit of thinness, often to the point of starvation. In DSM-IV (1994), the criteria consist of a persistent refusal to maintain body weight at or above a minimum expected weight (< 85% of expected weight) or a failure to gain the expected weight during a period of growth. The patient exhibits disturbance of body image, fear of becoming fat, and peculiar behavior regarding food. They hide food all over the house and frequently carry large quantities of candies in their pockets. Ritualistic exercising, extensive cycling, walking, jogging, and running are common activities [2].The onset of anorexia nervosa usually occurs between the ages of 10 and 30 years, with the maximum frequency at 17 to18 years of age. About 85% of all anorexia nervosa patients have the onset of the illness between the ages of 13 and 20 years. Amenorrhoea has been included as a diagnostic criterion for females in DSM III R (1987) and DSM IV (1994) [1]. However, Garfinkel et al [3], using data from a large community epidemiological survey, found that amenorrhoea did not discriminate between women with anorexia nervosa and women with all the features except amenorrhoea across a number of relevant variables. Unfortunately, the term “anorexia” , meaning loss of appetite, is a misnomer, because the loss of appetite is usually rare until late in the disorder. Evidence that the patients are constantly thinking about food is their passion for collecting recipes and preparing elaborate meals for others. Some patients cannot continuously control their voluntary restriction of food intake, and so they have eating binges [1].

•  SUBTYPES
DSM-IV (1994) introduced a new item related to the identification of two types of anorexia nervosa, the ‘restricting type' and the ‘binge eating-purging type' . Binge eating-purging is common among anorexia nervosa patients and it develops in up to 50% of them. They share many features with persons who have bulimia nervosa, they tend to have families in which some members are obese, and they are likely to be associated with substance abuse, impulse control disorders, and personality disorders. Restricting anorexia nervosa persons limit their food selection, take in as few calories as possible, and often have obsessive-compulsive traits. Both types of persons are preoccupied with weight and body image, they may exercise for hours every day, exhibit bizarre eating behaviors, and may be socially isolated, depressive and with diminished sexual interest. Some anorexia nervosa persons purge but not binge [1].

•  COURSE AND THERAPY
The course of anorexia nervosa varies greatly : spontaneous recovery without treatment, recovery after a variety of treatments, a fluctuating course of weight gains followed by relapses, a gradually deteriorating course resulting in death caused by complications of starvation. Studies have shown a range of mortality rates from 5 to 18 percent. Dynamic expressive-supportive psychotherapy is sometimes used in the treatment of anorexia nervosa patients. Many clinicians prefer cognitive-behavioral approaches to monitor weight gain and maintenance and to address eating behaviors. Pharmacological studies have not yet identified any medication resulting in definitive improvement. Some reports support the use of cyproheptadine, a drug with antihistaminic and antiserotonergic properties, in the restricting type of anorexia nervosa. Amitriptiline (mainly noradrenergic antidepressant), has been reported to have some benefit. Clomipramine (mainly serotonergic antidepressant), pimozide, and chorpromazine (classical antipsychotics), have not yielded positive responses. Uncontrolled trials of fluoxetine (a selective serotonin reuptake inhibitor), have resulted in some reports of weight gain [1].

1.5. EPIDEMIOLOGY

Eating disorders of various kinds have been reported in up to 4% of adolescent and young adult students. Anorexia nervosa is estimated to occur in about 0.5 to 1% of adolescent girls (less than 0.1% of the general population). It occurs 10 to 20 times more often in females than in males. Anorexia nervosa, although less common in men than in women, appear to display striking similar features in affected individuals of the two genders [5]. Although the disorder was initially reported most often among upper classes, recent epidemiological studies do not show that distribution. A recently reported case controlled study from the Aberdeen psychiatric case register found no class differences between cases of affective disorders and cases of anorexia nervosa [6]. It seems to be most frequent in developed countries, and it may be seen with greatest frequency among young women in professions that require thinness, such as modelling and ballet. In a large epidemiological study in the female population of northeast Scotland , it was found the that rates of refferal for female subjects with anorexia nervosa have been greatly increased since the 1960s. These rates likely reflect a genuine increase in incidence, but the data suggest that less severely ill patients are now being referred [7]. However, Willi et al [8], did not find an increase in incidence between 1973-1975 and 1983-1985, in the canton of Zurich in Switzerland.

1.6. FAMILY AND TWIN STUDIES:

A genetic component to anorexia nervosa was first considered when Theander [9] in 1970, noted the increased prevalence in the sisters of sufferers. There is a significantly higher frequency of anorexia nervosa in first-degree relatives of anorexic patients (3.22%) than in the relatives of controlled patients (0.02%) [10]. Twin studies indicate a greater concordance of anorexia nervosa in monozygotic twins (33 to 56%) than dizygotic twins (0 to 11%) [11, 12]. Using genetic modelling techniques on these data, Treasure & Holland [13] in 1991, estimated a heritability of 76% for anorexia nervosa. The same authors used the Eating Disorder Inventory to explore the heritability of anorexia nervosa in a female twin sample in which at least one twin was affected. They obtained high values for two of the subscales; the ‘drive for thinness' and ‘body dissatisfaction' subscales had heritability estimated of almost 100%. Rutherford et al [14] administered the Eating Disorder Inventory to 147 normal monozygotic and 99 normal dizygotic twin pairs. A heritability value of 41% was obtained for the overall scores, while the “body dissatisfaction” and “drive for thinness” subscales had heritability values of 52% and 44% respectively. Walters et al [15] in 1995, explored the epidemiological characteristics and risk factors of anorexia nervosa administering structured interviews to a population based on a sample of 2.163 female twin. Lifetime prevalence estimates of 0.51%, 1.62%, and 3.70% were obtained for the computer narrow, clinical narrow, and clinical broad diagnoses, respectively. Co-twins of twins with anorexia nervosa were at significantly higher risk for lifetime anorexia nervosa, bulimia nervosa, major depression, and current low body mass index. Significant comorbidity was found between anorexia nervosa and major depression, bulimia nervosa, generalized anxiety disorder, alcoholism, phobias, and panic disorder. Finally, Gorwood et al [16] in 1998, in a meta-analysis study, found 55 non-systematically recruited twin studies (with at least one patient affected with anorexia nervosa), describing 66 monozygotic and 24 dizygotic twins. Concordance rates were 44% for monozygotic and 12.5% for dizygotic twins. The four systematically recruited twin studies showed that 20 out of 40 monozygotic twins (50%) were concordant for anorexia nervosa versus one out of 32 dizygotic twins (3%).

1.7. ETIOLOGY

Biological, social, and psychological factors are implicated in the causes of anorexia nervosa.

1.7.1. BIOLOGICAL FACTORS: Twin studies (have already discussed), caloric requirements, neurotransmitter dysregulations (are discussed extensively bellow), CT & PET findings, and hormonal (FSH, LH,TSH,CRH) suppression indicate the biological component of etiology. It seems that anorexic patients may have abnormal caloric requirements. To maintain stable weight after weight restoration, restricting anorexic patients require a significantly higher caloric intake than do bulimic anorexic patients. Elevated caloric requirements, when coupled with reduced food intake, may particularly contribute to relapse in these anorexic patients [17]. Furthermore, CT studies reveal enlarged sulci and ventricles in anorexia nervosa patients during starvation, a finding that is reversed by weight gain [18]. In one PET- scan study, caudate nucleus metabolism was higher in the anorectic state than after the episode [1]. The hypothalamic-pituitary-gonadal axis (HPG) has excited particular interest because amenorrhea is a central feature of anorexia nervosa and its onset and recovery show some dissociation from weight; as many as 25% of cases develop amenorrhea prior to significant weight loss and even following weight restoration there may be considerable delays in the re-establishment of normal menses. The levels of gonadotropins, luteinizing hormon (LH) and folicle-stimulating hormone (FSH), are uniformly low which increase with weight recovery in most but not all patients. The levels and the circadian pattern of LH, FSH and oestrogens, in the emaciated anorexic is similar to that in the pre-pubertal state. In addition, anorexia nervosa mainly occurs in the age of puberty. The onset of mammalian female puberty requires the functional activation of a specialized group of hypothalamic neurons that produce luteinizing hormone-releasing hormone (LHRH), the neurohormone governing sexual maturation and reproductive function. A combination of a decrease in transynaptic inhibitory tone (via GABA and opioid peptides) and an increase in excitatory inputs (via norepinephrine and neuropeptide Y) to LHRH neurons is thought to be instrumental in bringing about the initiation of puberty. Recent studies have raised the possibility that glial cells may also play a role in the control of LHRH. The finding that about 50% of glial cells have estrogen receptors further supports the notion of a direct action of estrogen on hypothalamic astrocytes [19]. The hypothalamic-pituitary-adrenal axis (HPA) has also been the subject of much study particularly in view of its disturbance in affective disorder as well as in anorexia nervosa. An elevation of 24h mean plasma cortisol concentrations is well established and also raised levels of free-cortisol in the urine. The cortisol production rate of patients with anorexia nervosa declines with slight weight gain, a finding opposite to that noted when malnourished non-anorexic persons gain weight on refeeding. The majority of anorexics fail to suppress cortisol normally following the administration of dexamethasone. Elevated CSF levels of corticotropin-releasing hormon (CRH), further support the hypothesis that the hypercortisolism of anorexics reflects a defect at or above the hypothalamus. A hyperdynamic HPA axis is not a feature of simple malnutrition but its significance in anorexia nervosa is still unclear. Finally, many anorexic patients demonstrate the low triiodothironine (T3) syndrome which is also seen in malnutrition. This syndrome probably contributes to a number of clinical features of anorexics including the low basal metabolic rate, dry skin, tachycardia and elevated serum cholesterol [1].

1.7.2. SOCIAL FACTORS: Anorexia nervosa patients find support for their practices in society's emphasis on thinness and exercise. No family constellations are specific to anorexia nervosa.

1.7.3. PSYCHOLOGICAL FACTORS: Psychoanalytic clinicians who treat patients with anorexia nervosa generally agree that those young patients have been unable to separate psychologically from their mothers. The body may be perceived as though it were inhabited by an introject of an intrusive and unempathic mother. Starvation may have the unconscious meaning of arresting the growth of that intrusive internal object and thereby destroying it.

The multifactorial model of anorexia nervosa

2. NEUROTRANSMITTER SYSTEMS WHICH MAY BE INVOLVED IN GENETIC SUSCEPTIBILITY TO ANOREXIA NERVOSA

2.1. DOPAMINERGIC SYSTEM: The first argument for the involvement of the dopaminergic system is suggested by the findings that Apomorphine (D2 agonist), L-Dopa (enhancing dopamine synthesis), and amphetamine (releasing dopamine from presynaptic stores) have been shown to be anorexigenic , an action selectively blocked by dopamine antagonists such as haloperidol and chlorpromazine. Second, weight loss of the anorectic patient is often associated with hyperactivity and distortion of body image. Dopamine agonists (such as amphetamine) lead to both loss of appetite and hyperactivity. Third, in amenorrhoea, a decrease in blood oestrogen and luteinizing hormone (LH) and the absence of cyclical secretion of LH has been observed in female anorectic patients. Dopamine agonists inhibit LH-RH and stimulate the secretion of prolactin. Fourth, some clinicians [20] consider anorexia nervosa as a pathology belonging to the spectrum of ‘addictive behaviors'. Dopamine is released in anticipation of feeding, and many experimental data show the implication of mesolimbic dopaminergic systems in behavior reward and reinforcement. Furthermore, Ebstein R P et al [21] in 1997, found that, both Dopaminergic and serotonergic (5HT-2C) receptor gene polymorphisms are associated with the human personality trait of ‘reward dependence' assuming that the relationship between 5HT and dopaminergic activity presumed to exist for the regulation of drug-induced motor activity extends to the regulation of brain stimulation-induced reward. Finally, knock-out mice give many interesting informations: Mice with an inactivated tyrosine hydroxylase gene are born hypoactive and stop feeding a week after birth [22]. Absence of D2 receptors leads to animals that are akinetic and bradykinetic in behavioral tests, but absence of D3 receptors leads to mice that are hyperactive in exploratory tests [23, 24]. Lastly, dopamine transporter (DAT) lacking mice result in hyperlocomotion, low weight, and no effect of amphetamine and cocaine [25]. The dopaminergic system may thus intervene not only in the general scheme of anorexia nervosa (eg the anorexigenic effects of dopamine agonists), but also in the more specific characteristics such as amenorrhoea, hyperactivity, distortion of body image, and in traits suggesting a possible addictive tendency in behavior.

2.2. NORADRENERGIC SYSTEM : The possible role of catecholamines in hypothalamic regulation as well as affective disorders suggest that noradrenaline could participate in the genesis of anorexia nervosa [26]. For example, amphetamine, which block reuptake of NA, reduces hunger sensation and food intake in a dose dependent manner in humans. Hypothalamus is largely innervated by noradrenergic fibers. Furthermore, it is known that NA is involved in secretion of gonadotrophines, reduces the secretion of CRH, participates in the hypothalamic control of TRH secretion, and it is also regulates the hypothalamic liberation of vasopressin.

2.3. OPIATE, AND OTHER SYSTEMS : Evidences that endogenous opiate activity could contribute to a deregulation of eating behavior exist. Administration of opiate agonists increases food intake in rats whereas antagonists decrease feeding behavior. Similarly, administration of opiate antagonists, such as naloxone, in humans diminish food intake. Different peptides appear to influence appetite control. Neuropeptide Y (NPY), for example, infused in the CNS of rats leads to significant food consumption, while infusion of cholocystokinin (CCK) decreases food intake in both animals and man. Genetic factors appear to be also involved in the deposition to store fat and the way body uses dietary energy. The ob gene encodes for leptin, a fat-secreted hormone secreted by adipocytes which regulates ingestive behavior and energy balance. Ob gene thus also belongs to candidate genes in anorexia nervosa, and has been recently localized in humans on chromosome 2p21 [27]. Leptin emerges as a hormone that may not only control food intake and energy expenditure but may also regulate neuroendocrine function and certain aspects of human behavior. Moreover, falling leptin concentrations may contribute to the pathophysiological implications of restrained eating and binge eating [28]. Von Prittwitz et al [29] in 1997, in the only study which identify a relationship between a score on a psychometric scale and leptin levels, determined the serum leptin levels in 136 underweight and 49 overweight students, who completed the Three-Factor Eating Questionnaire. They found that individuals with high restraint scores have lower serum leptin concentrations than low scoring subjects.

2.4. SEROTONERGIC SYSTEM

2.4.1. Neurochemical evidences : It seems clear that 5-HT is involved in the regulation of human eating, as it is in animals. Fenfluramine, a serotonin agonist, reduces appetite and increases satiety, while ritanserin, a 5-HT2 antagonist neutralize this anorexigenic effect [30]. Intraventricular injections of neurotoxins that block or destroy serotonergic neurons also provoke hyperphagy. 5-HIAA concentrations in the CNS of anorectic patients showed reduced levels and normal levels after weight gain. Brewerton et al [31] found that anorectic women showed a decrease in prolactin response after stimulation with l-tryptophane or mCPP (serotonin agonists)in the acute phase as well as after weight gain compared to controls who did not show a decrease prolactin response. Increased tryptophan levels in plasma and CSF of anorectic cancer, uremic, and cirrhotic patients have been reported. It is conceivable that the increased brain tryptophan concentrations, and the consequent increased brain serotonergic activity, may mediate the onset of anorexia in these patients [32]. Ingestion of glucose (pure carbohydrate) will lower plasma tryptophan but increase the ratio of tryptophan to other large neutral amino acids (LNAA). This rise in the tryptophan ratio is blocked by the addition of protein. People with severe obesity have lower plasma tryptophan ratios than lean subjects. In underweight anorexics a carbohydrate meal fails to raise the plasma tryptophan level in comparison with the level in normal controls, while a protein meal causes a marked drop in the tryptophan ratio. These data would imply a reduced availability of tryptophan of the brain. In keeping with these findings, there is a low level of the serotonin metabolite 5HIAA in the CSF of underweight anorexics, which normalize after weight gain. These findings are in different direction with the above Laviano's hypothesis but they also support the suggestion that serotonin neurons in the brain are somehow involved in physiological and behavioral responses to diatery adjustments. Treasure J [33] in 1997, proposed a physical animal model which indicate the central role of 5-HT in anorexia nervosa. She described a syndrome in pigs which resemble that of anorexia nervosa in humans. The affected animals restrict their intake of normal food, and spend more time on nonnutritive hyperactive behavior. Interestingly, the psychoactive drug amperozide (a 5-HT receptor antagonist) prevents and successfully treats these condition [34]. Serotonin may also be involved in important symptoms of anorexia nervosa, such as the initial onset of anorexia nervosa which can be associated with a stressful event, the psychosexual immaturity, the predominance in females, the obsessional premorbid personality, and the comorbidity between anorexia nervosa and depressive disorders.

2.4.2. Serotonergic system and Stress, in patients with Anorexia Nervosa : Brain 5-HT neurons discharge in a slow and rhythmic manner that is a manifestation of their endogenous pacemaker activity. This regulation firing during waking creates a steady synaptic release of 5-HT which provides a tonic excitatory drive that modulates motor system neuronal activity. The anticipation of motor activity by 5-HT neurons suggest that they serve a priming function for motor output. Furthermore, 5-HT's involvement in autonomic and neuroendocrine regulation serves a support function for the demands of changes in the level of motor output, such as increased oxygenation of the blood and increased carbohydrate consumption for maintaining a stable glucose supply to the brain. Illness onset of anorexia nervosa is frequently marked by stressful events, such as in many psychiatric disorders, with serotonin playing a critical role in the response to stress [35].

2.4.3. Serotonin and psychosexual immaturity in anorexia nervosa: Psychosexual immaturity as well as the experience of conflicting sexual feelings are, according to many authors, at the heart of anorexia nervosa. Serotonin has been shown to inhibit sexual behavior in certain species, for example in the rat after destruction of serotonergic pathways in the ventro-medial hypothalamus. Furthermore, the penile erection caused by 5-HT receptor agonists is mediated by 5-HT-2C receptors, and 5HT-2A receptor stimulation suppresses sexual performance. Bagdy et al [36], found that stimulation of 5HT-2C receptors in rats induces excessive grooming, penile erection and increased oxytocin secretion, and that stimulation of 5HT-2A receptors causes a further increase in plasma oxytocin concentration, but inhibits grooming and penile erection.

2.4.4. Sex-dependent effects of serotonin and oestrogens and their relation with anorexia nervosa : The hypothesis of serotonin involvement in anorexia nervosa has been further supported from the fact that serotonin circuits show variations that are partially sex-dependent. For example, d-fenfluramine and mCPP have greater hypophagic effect in the female rats. Variations during menstrual cycle and secretion of prolactin during food restriction exist only in females. Serotonergic mechanisms are implicated in behaviors (aggression, sexual behavior, impulse control) and psychiatric disorders (depression, eating disorders, suicide) which are related to gender. Some data are available about gender differences in serotonargic activity: High-density [3H]imipramine binding sites, which are located on the presynaptic serotonergic terminals, are more concentrated in female than in male rats. Tryptophan, serotonin, and 5-HIAA are present in higher levels in females than in males in several rat brain regions. There are similar gender differences in the level of 5-HIAA in the CSF of patients with chronic pain or depression [37]. Some investigators report concentrations of serotonin reuptake sites in platelets which are higher in healthy women that man, and in post-mortem studies seems that gender influences frontal [3H]imipramine binding sites, particularly in the right orbital cortex [38]. These animal and human data support the hypothesis of a higher serotonergic activity, at least at the presynaptic level, in females compared to males. Biver's et al [39] PET findings, support the evidence for the high presynaptic activity of the female serotonin system and the consequent apparent ‘down-regulation' of 5HT2 receptors in women compared to men. These results support the view that distinct liability for men and women to suffer from some psychiatric diseases responding to serotonergic agents may be related to differences in brain serotonin receptors.

Furthermore, oestrogen is thought to exert powerful effects on mood, mental state and behavior in women. The role of oestrogen in affective disorders is suggested by the fact that menopausal and postnatal depression are associated with a massive drop in plasma oestrogen concentrations, and oestrogen has been reported to be effective in the treatment of Depression and Alzheimer's disease in women. Differences in the age of onset and symptoms of schizophrenia in women compared with men has also implicated oestrogen in schizophrenia. Recent reports have been shown that oestrogen can stimulate a threefold increase in the amount of 5HT-2A receptor messenger RNA in the dorsal raph nucleus of the female rat. In addition, the binding sites were increased in anterior frontal, anterior cingulate and the primary olfactory cortex and nucleus accubens, essential brain regions for cognition, emotion, and neuroendocrine control [40]. These findings indicate that the acute effects of oestrogen on mood and mental state are mediated at least in part by an increase in density of the 5HT-2A receptors.

2.4.5. Serotonin and obsessional tendencies in patients with anorexia nervosa : The personality trait more frequently found in anorectic patients is ‘neurotic perfectionism' as well as ‘obsessional tendencies', which could both be considered similar to the ‘pain-avoidance' dimension described by Cloninger [41], a dimension defined by the author as a marker for an abnormal serotonin function. Obsessional personality traits and symptoms have been reported in between 3% to 83% of eating-disordered cases, the results being dependent on the criteria [42]. Up to 30% of anorexia nervosa patients have been reported to have significant obsessional personality features at first presentation. Hudson et al [43] found that a diagnosis of Obsessive-Compulsive Disorder (OCD) can be made in as many as 69% of restrictor and 44% of bulimic anorexics. Recent studies have found a high rate of OCD in anorexics several years after the reported onset of the eating disorder, and 20% continued to meet criteria for OCD after weight restoration. In addition, anxiety disorders are common in all anorexics with rates of 39% to75%. The hypothesis that 5HT is related to the pathobiology of OCD was initially derived from the observation that the potent serotonin reuptake inhibitor (SRI) chlomipramine, and the later introduced serotonin selective reuptake inhibitor (SSRI) fluoxetine, was effective in relieving OC symptoms. The results of pharmacological treatment trials and studies of biological markers indicate that dysregulation of the 5HT system may be involved in the pathogenesis of OC symptoms. Blunting of neuroendocrine responses to 5HT agonists and increase of 5HT functioning after treatment with SSRIs (eg. fluoxetine), suggest that, the primary deficit in OCD is a decreased 5HT responsivity. Exacerbation of OC symptoms after mCPP challenge is not entirely consistent with this hypothesis, however, behavioral hypersensitivity coupled with neuroendocrine hyposensitivity to serotonergic stimulation might characterize the serotonergic dysfunction of OCD [44]. Taken together, malnutrition and weight loss are associated with a severe increase in the intensity of depressive, anxious, and obsessive symptoms in underweight anorexics. Whether persistent symptoms after long-term weight restoration from anorexia nervosa reveal an underlying psychobiological trait, or are related to good outcome remains uncertain. In any event, the major comorbidities of anorexia nervosa (depression, anxiety, and obsessionality) may contribute to starvation and weight loss, which in turn, may exacerbate these symptoms. That is, anorexics may enter a vicious cycle in which the symptoms make the malnutrition worse, and the malnutrition makes the symptoms worse [45].

2.4.6. Serotonin and depression in patients with anorexia nervosa : The comorbidity between anorexia nervosa and depressive disorder (in which serotonin may be implicated) also underlines the potential role of serotonin in the genesis of anorexia nervosa. These two disorders both exhibit weight loss, insomnia, loss of libido, depressed mood, disturbance in concentration, and also demonstrate abnormalities in sleep architecture and endocrine function. In fact, as many as 91% of malnourished anorexics suffer from depressive disorders. In comparison, 15% to 58% of patients continue to exhibit some degree of depressive disturbance after weight restoration . Abnormalities of both serotonergic neurotransmission and hypothalamic-pituitary-adrenal (HPA) axis activity are found in both depression and eating disorders and may play important pathogenic roles. Both conditions are frequently associated with elevated plasma cortisol levels and insensitivity to glucocorticoid (dexamethasone) feedback, presumed to be caused by increased central drive on the HPA axis. Abnormal 5HT neurotransmission is also believed to be a key factor in depression. Many clinically effective antidepressants alter 5HT neurotransmission, improving both mood and hypercortisolemia in depressive patients. Serotonergic drugs, like chlomipramine and fluoxetine, also provide therapeutic effects in patients with anorexia nervosa supporting the evidence that serotonergic system is a key factor in the pathogenesis of anorexia nervosa [43, 45].

2.4.7. Involvement of serotonin in impulsivity, aggression and suicidality. What's the common in anorexia nervosa? Suicidal behavior is a prevalent symptom associated with depression. A number of reports have suggested that an abnormality in central serotonergic activity may be associated with suicidality. Studies of suicide attempters have demonstrated low CSF 5HIAA in patients with a history of violent suicide attempts [46]. Post-mortem studies have demonstrated decreased levels of serotonin and decreased imipramine binding in the brains of suicide victims as compared to accident victims. A significant decreased prolactin response to d,l-fenfluramine, interpreted as reduced net central serotonergic activity, is found in depressed as well as personality disordered patients compared to controls and associated with suicide in both cohorts [47]. Type 2 serotonin receptor (5HT-2) are widespread in the human cortex and appear modified in the frontal lobe of patients who suffer from depression or who die from suicide [48, 49]. Studies of non-suicidal self-injurious behavior have demonstrated low CSF 5HIAA in depressed patients with self-injurious behavior compared to those without. New et al [50] in 1997, have hypothesized that the abnormality in central serotonergic activity that has been associated with suicidal behavior might be associated with the more broadly defined category of ‘self-directed aggression', not necesserily with suicidal intent. The main clinical feature of patients with anorexia nervosa (limit of food intake) can be viewed as a self-directed aggression which may mediated by the serotonergic system. There is a recognized association between various types of self-mutilation (e.g. cutting and burning) and eating disorders [51]. In addition, evidences suggest that impulsive aggression is both partially heritable and associated with abnormalities in serotonergic functioning [52]. The selection of genes involved in serotonin functioning as candidate genes for influencing these behaviors comes from the observation that decreased serotonergic activity has been associated with ‘impulsive aggression'. Nielsen et al [53], found a significant association between tryptophan hydroxylase genotype and CSF 5HIAA concentration in one impulsive group, but no association of tryptophan hydroxylase genotype with impulsive behavior was detected. New et al [54] in 1998, assessed the relationship between ‘impulsive aggression' and tryptophan hydroxylase genotype in a clinical sample with personality disorders. It was conclude that ‘impulsive-aggressive' behavior in male personality disorder patients may be associated with the tryptophane hydroxylase genotype.

2.4.8. Serotonin and Schizophrenia. Are there common pathways in anorexia nervosa? 5HT-2A receptors are involved in the actions of hallucinogenic drugs and have been implicating in the pathogenesis and treatment of schizophrenia. An important property of clozapine's atypicality is that this antipsychotic drug is an effective 5HT-2A antagonist. Clozapine administration decreases 5HT-2A mRNA and ketanserin binding sites. Some recent genetic association studies have found a positive association between schizophrenia and the 102T/C polymorphism of the 5HT-2A receptor gene [55, 56]. Jakab et al [57] in 1998, studying in primates, found that 5HT-2A receptors accumulated in the apical dendritic ‘bottle-neck' segment of pyramidal cells have a strategic role in controlling the rate of dendritic currents. This apical dendritic gating mechanism may play an important role in working memory and latent inhibition. Excessive 5HT-2A receptor activation, in this region, may be disruptive. The 5HT-2A agonist ‘Ecstasy' can induce hallucinations and delusions because of the excessive rate of dendritic currents reaching the soma. It was hypothesized that hyperactive pyramidal cells may produce the ‘positive' hallucination-like symptoms observed in schizophrenia due to a dysfunctional 5HT-2A receptor system in their apical dendrites. In the case of anorexia nervosa, the main clinical feature ‘disturbance of body image' as well as the secondary symptoms ‘fear of becoming fat' and ‘peculiar behavior regarding food' seem to have a delusional dimension or even a schizophrenic-like dimension. Similar symptoms with disturbance in body image and generally peculiar behavior are common in schizophrenics. In conclusion, 5HT-2A receptor system may provide common pathways, in the pathogenesis of both anorexia nervosa and schizophrenia. Clozapine's efficacy in schizophrenia and serotonergic antidepressant's efficacy in anorexia nervosa support this hypothesis.

2.4.9. Obesity, Anorexia Nervosa, and Serotonergic system : The regulation of body weight involves coordination of intake and expenditure of calories. Control over this process is highly complex , however, and involves multiple neural circuits with specific neuropeptides, neurotransmitters, all influenced by peripheral signals, such as leptin, and input of higher cortical centers. Identification of molecules that participate in these central regulatory circuits is accelerating and the list now includes leptin, the leptin receptor, melanin concentrating hormone, the melanocortin 4-receptor , urocortin, and neuropeptide Y and its type 5-receptor [58]. In addition, there are many indications that obesity is a genetic disease which results when a variety of environmental factors act on multiple genes to influence our eating, metabolism and energy expenditure. During the past years, researchers have linked mutations in five different genes (ob, db, tub, A-y, and fat) to obesity in mice [59]. Isolated cases of obesity in humans have recently been identified which also result from a mutation in some of these genes [60]. All these known genes regulate body fat mainly by affecting appetite. Mutations in any of these five genes cause a significant increase in food intake. For example, ob mice eat 62% more food than normal mice, and agouti yellow (A-y) mice consume 36% more food than controls. However, Dong & Wagner [61] in 1998, found that ICAM-1 -/- mice develop a maturity-onset obesity without an obvious increase of appetite. Recent data have suggested that adipocytes synthesize and secrete a 16 kDa peptide (leptin) which acts centrally to regulate weight gain by suppressing appetite. To exert such effects, it may acts as an endogenous ligand in the CNS, since specific receptors (Ob receptors) have been recently reported to be widely distributed in the brain. On this basis, Costa et al [62] suggested that leptin may act to regulate appetite at least in part by directly modulating the secretion of CRH from the hypothalamus.

Most of the research in the neurotransmitter area has focused on the serotonergic system. Weight gain is a relevant side-effect of treatment with the atypical neuroleptic drug clozapine. Some clinicians found that weight gain on clozapine tender to be greatest in patients who had the best clinical response [63]. The mechanisms of the weight gain are poorly understood, but some hypothesis have been suggested. Neuroleptics (mainly the low potency antipsychotics, chlorpromazine, and thioridazine as well as the atypical clozapine) block serotonergic transmission [64]. Patients frequently report an inability to suppress appetite after a full meal, suggesting a change in satiety perception. Bromel et al [65] in 1998, found that overeating and weight gain in predisposed schizophrenics treated with clozapine was related with elevated leptin secretion. Leptin, has been shown to correlate with the body mass index, and is presumed to signal the size of the adipose depot to brain and peripheral tissues. The authors of the above study assumed that in predisposed individuals central effects of clozapine induce increased appetite and as a consequence overeating. Both overeating and the ensuing gain in fat mass induce the increased leptin secretion. In addition, hyperglucemia and ketoacidosis, in predisposed patients, are some rare relative side-effects of clozapine [66]. In women with anorexia nervosa serum leptin levels are reduced significantly in association with low body fat and weight, suggesting that the regulation of leptin is maintained even at an extreme of low body weight and fat in subjects with anorexia nervosa [67]. Summarizing, energy balance, appetite, food intake, weight gain and the extreme condition of obesity share at least some pathogenic pathways regulating by the serotonergic system. Anorexia nervosa is another extreme condition in relation to weight, appetite, and food intake. It is possible that some common pathogenic pathways, involving serotonergic system, may participate in the pathogenesis of both these conditions.

SCHIZOPHRENIA

Introduction

Schizophrenia is the most severe of the mental disorders and although is discussed as if it was a single disease, the diagnostic category can include a variety of disorders that present with somewhat similar behavioral symptoms. Schizophrenia is frequently characterized by a chronic recurrent course and probably comprises a group of disorders with heterogenous causes and definitely includes patients whose clinical presentations, treatment responses, and courses of illness are varied. It occurs in all cultures, the incidence is about 2 to 4 cases per 10,000 population per year and the life time risk is about 1%. With conventional antipsychotic agents, at least 30% of schizophrenic patients exhibit an inadequate or poor response. Moreover as many as 60 % experience relapse after 1 year of therapy.

DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

The major brain areas implicated in schizophrenia are the limbic structures, the frontal lobes and the basal ganglia. The thalamus and the brainstem have also been implicated because of the role of thalamus as an integrating mechanism and the fact that the brainstem and the midbrain are the primary locations for the ascending aminergic neurons. For decades, the biochemical basis of schizophrenia and the mechanism of action of antipsychotic drugs was overly concentrated on the role of dopamine. The simplest formation of the dopamine hypothesis of schizophrenia posits that schizophrenia results from too much dopaminergic activity. The theory involved out of two observations. First, the efficacy and the potency of classical antipsychotics is correlated with their abilities to act as antagonists of the dopamine type 2 (D2) receptor. Second, drugs that increase dopaminergic activity, most notably amphetamine, are psychomimetics. Another positive association between the clinical efficacy of antipsychotics and their dopamine receptor activity is suggested by the effects of the drugs on the plasma concentration of homovanillic acid, the major metabolite of dopamine. Several studies have reported that high pretreatment concentrations of plasma homovanillic acid are positively correlated with an increased likelihood of a favorable clinical response. Furthermore, a decrease in plasma homovanillic acid concentrations early in the course of treatment is correlated with favorable clinical response. However, this basic theory, does not elaborate on whether the dopaminergic hyperactivity is due to too much release of dopamine, to many dopamine receptors, hypersensitivity of the dopamine receptors to dopamine, or some combinations of those mechanisms. Nor, this basic theory, specify which dopamine tracts in the brain may be involved, although the mesocortical and mesolimbic tracts are most often implicated.

Although the dopamine hypothesis of schizophrenia has stimulated schizophrenia research for more than two decades and remains the leading neurochemical hypothesis, it is difficult to explain the fact that dopamine antagonists are effective in treating virtually all psychotic and severely agitated patients, regardless of diagnosis. It is also difficult to explain the fact that although the dopamine receptor blocking effects occurs immediately, the full antipsychotic effects of the drugs may take weeks to develop. It is not possible, therefore, to conclude that dopaminergic hyperactivity is unique to schizophrenia.

DOPAMINE RECEPTOR ANTAGONISTS: CLASSICAL OR TYPICAL ANTIPSYCHOTICS

A diverse group of drugs that blockade the dopamine 2 (D2) receptor are commonly referred to as antipsychotic drugs. Reserpine , is historically the first effective antipsychotic drug. In 1931, Sen and Bose published the first paper reporting the effectiveness of rauwolfia in hypertension and mania. In 1953, the active ingredient, reserpine, was identified and quickly entered into the then limited pharmacological approaches to psychosis. Chlorpromazine, a phenothiazine derivative that was later shown to be a dopamine receptor antagonist, was the first so-called classical or typical antipsychotic to be synthesized in the early 1950s and to enter widespread clinical use. Not counting reserpine, seven classes of drugs are generally considered typical antipsychotics: 1. Phenothiazines , are typed according to the nature of the side chain: aliphatic (for example, chlorpromazine), piperazine (for example, fluphenazine) and piperidine (for example, thioridazine). 2 .Thioxanthenes : chlorprothixene and thiothixene. 3. Dibenzoxazepines : loxapine (which, although have structural similarities with clozapine, the two compounds have different pharmacodynamic properties, and loxapine is clearly classifiable with dopamine receptor antagonists, whereas clozapine is not). 4. Dihydroindol : molindone. 5. Butyrophenones : haloperidol (the most widely used antipsychotic) and droperidol. 6. Diphenylbutylpiperidine : pimozide , and 7. Benzamides : sulpiride, raclopride (which has been used mainly as a radio-labeled ligand in PET studies), and remoxipride (that has specific receptor activity at D2 receptors and sigma receptors).

Although the pharmacokinetic properties of the classical antipsychotics vary widely (half-life range from 10 to 20 hours), the most of them can be given in one daily oral dose once the patient is in a stable condition and has adjusted to any adverse effects. Studies using the PET techniques in patients who were taking a variety of antipsychotics in different dosages have produced data indicating that occupancy of about 60% of the D2 receptors in the caudate-putamen is correlated with clinical response and that occupancy of more than 70% of the D2 receptors is correlated with the development of extrapyramidal symptoms. Other investigators have reported that theoritically adequate occupancy of D2 receptors can be found in patients who are still non responsive to antipsychotic drugs, thus indicating that occupancy of D2 receptors is not the only variable in clinical response.

The introduction of antipsychotic drugs revolutionized the treatment of schizophrenic patients and other seriously ill psychotic patients. The use of the classical antipsychotics results in significant clinical improvement in 50 to70% of psychotic patients, and almost 90% of psychotic patients receive some clinical benefit from the drugs. Nevertheless, most of the classical antipsychotics have significant effects on other receptors, including adrenergic, cholinergic, and histaminergic receptors. The α -1 adrenergic antagonist activity of many of the classical antipsychotics can result in vasodilation and orthostatic hypotension, the blockade of muscarinic cholinergic receptors results in dry mouth and constipation, and the imbalance of adrenergic - cholinergic activity and the increased prolactine levels result in sexual dysfunction. Finely, the classical antipsychotic drugs are associated with a number of uncomfortable and potentially serious neurological adverse effects. Neuroleptic-induced parkinsonism, dystonia and acute akathisia are common neurological adverse effects, during the first weeks of treatment and represent an imbalance of adrenergic - cholinergic - dopaminergic systems caused by the antipsychotics. Other serious neurological adverse effects include: the neuroleptic-induced tardive dyskinesia, the neuroleptic malignant syndrome, the risk of inducing a seizure and the sedation.

THE SEROTONIN - DOPAMINE INTERACTION IN SCHIZOPHRENIA

•  The dopamine and the serotonin system

The dopaminergic system arises from groups of cell in the midbrain. Neurons from the substantia nigra ascend to the striatum via the nigrostriatal pathway, and are primarily involved in the modulation of motor behavior, whereas neurons from the ventral tegmental area project to the limbic and cortical regions (mesolimbic and mesocortical projections) and are involved in cognition and modulation of motivation and reward. The effects of dopamine are mediated through a series of dopamine receptors, the D1 family (D1 and D5), which mediate the dopamine-stimulated increase of adenylate cyclase, and the D2 family (D2, D3, D4) which mediate effects that are independent of D1-mediated effects and also exert an opposing influence on adenylate cyclase activity. The D1 receptors are prominent in the cortical regions, the D2 receptors are prominent in the striatum, and theD3 and D4 receptors have a higher distribution in the limbic regions.

The serotonergic neurons also arise from discrete midbrain nucleis. The dorsal raphe nucleus that project to the cortex and the striatal regions and the median raphe nucleus that project to the limbic regions. The serotonergic receptors are grouped on the basis of shared genetic sequences and second messenger systems in four groups : 1. The 5HT-1 family ( 5HT-1A, 5HT-1D, 5HT-1E and 5HT- 1F ) which uses G-protein - mediated signal transduction. 2. The 5HT-2 family ( 5HT-2A, 5HT-2B, 5HT- 2C , 5HT-4, 5HT-6, 5HT-7 ) which uses phosphoinositol - mediated signal transduction. 3. The 5HT-3 receptor which uses ion - gated channels and 4. The 5HT-5 family , a new group of 5HT receptors, which contains the 5HT-5A and 5HT-5B receptors.

•  Serotonergic inhibition of dopaminergic function in the midbrain and extrapyramidal symptoms. The effects of atypical antipsychotics.

Serotonergic projections from the dorsal raphe nuclei project directly to the substantia nigra and inhibit the firing of the dopaminergic neurons. This stimulation of dorsal raphe serotonergic fibers releases serotonin in the substanta nigra. This is associated with a decrease in the firing rate of the dopaminergic neurons, suggesting an inhibitory modulation of the dopamine neurons which seems to be modulated by 5HT-2 receptors located on the somatodendritic surface [4]. As expected, anatomical or chemical lesions that disrupt the raphe - nigral projection, 5HT-1A agonists that functionaly inhibit the raphe - nigral neurons, or 5HT-2 antagonists that antagonize the effect of the raphe- nigral system all lead to a biochemical and functional disinhibition of the dopamine system [5].

Neuroleptic - induced extrapyramidal symptoms (EPS) in humans result from occupancy of D2 receptors in the striatum. Neuroleptic - induced catalepsy in animals which represents a similar mechanism, provides a valuable model to study EPS. Since serotonin exerts an inhibitory influence on the dopaminergic system, manipulations that inhibit serotonin function would be expected to disinhibit the dopaminergic system and ameliorate catalepsy. Anatomical and chemical lesions of the raphe nuclei prevent and ameliorate neuroleptic - induced catalepsy in rodents [6]. 5HT-1A agonists, inhibit the firing of serotonergic neurons. Several studies [7] reported a beneficial effect of 5HT-1A agonists in reversing and preventing the development of catalepsy in animals. These findings suggest that the combination of a 5HT-1A - agonist and a D2 - antagonist may lead to EPS - free antipsychotic activity. Subsequent reports using specific 5HT-2 antagonists have confirmed a role for 5HT- 2 in alleviating catalepsy [7]. Ritanserin, a 5HT-2 antagonist, was able to antagonize haloperidol - induced catalepsy when induced with low doses of haloperidol but was ineffective when suprathreshold doses of haloperidol were used to induced catalepsy. Thus, 5HT-2 blockade may bestow only a limited protection from the effects of D2 blockade. Serotonergic agonists would be expected to further inhibit the dopamine system and worsen EPS. Thus, SSRIs enhance serotonergic transmission and worsen EPS in rodent and primate models [8].

Many reports have established clozapine s freedom from EPS in usual doses [9]. Is this related to clozapine s serotonin - dopamine interaction profile ? It has been postulated that clozapine s high ratio of 5HT-2 to D2 affinity may account for its diminished EPS [10]. PET studies suggest that patients receiving conventional neuroleptics experience EPS only when D2 occupancy exceeds a threshold somewhere in the range of 75-80 % D2 occupancy. Clozapine”s D2 occupancy varies from 20 to 67 % and has never been showed to exceed the putative threshold for EPS [11]. Thus clozapine s low EPS profile can be explained on the basis of its low D2 occupancy, and there appears to be no need to invoke the role of the serotonin - dopamine interaction to explain its superiority in alleviating EPS. There have been proposed [12] two hypothesis to explain how 5HT-2 antagonism prevents or alleviate EPS : 1. The addition of a 5HT-2 antagonist would shift the D2 occupancy curve to the right, thus increasing the dose at which the EPS threshold is crossed, and 2. 5HT-2 blockade may elevate the threshold for EPS, through the modulating influences on cholinergic or GABAergic mechanisms, without a direct effect on D2 occupancy. In the case of risperidone a series of doses from 4-8 mg / day, risperidone produces significantly fewer EPS than haloperidol. This superiority of risperidone in producing fewer EPS is not as striking as that of clozapine. The ability of HT-2 antagonism to counter the effects of D2 antagonism is limited. As the dose of risperidone is increased beyond 6 mg / day, suprathreshold D2 blockade may result, and the serotonin - dopamine interaction mechanism may no longer be able to alleviate EPS [13]. The therapeutic window observed in clinical trials with risperidone may not be peculiar to risperidone but may simply reflect limits of serotonergic protection in the face of high D2 dopamine blockade.

Serotonin - dopamine interaction and the effect of atypical antipsychotics in negative symptoms.

Serotonergic neurons that arise in the dorsal raphe nucleus project uninterruptly via the medial forebrain bundle to the striatum and cortex. Stimulation of these neurons or the striatal administration of serotonergic agonists, causes an inhibition of striatal neuronal firing. This effect seems to be mediated by the 5HT-2 receptors and may results from a decreased release or a decreased synthesis of dopamine. Lesions of the serotonergic projections or administration of 5HT-2 antagonists blocks serotonin s inhibitory action on striatal dopamine and results in increased dopamine levels in the striatum. [14,15]. In summary, there is convincing evidence that the serotonergic projections inhibit dopamine function in the striatum and cortex inhibiting the synaptic release of dopamine and probably the synthesis of dopamine. Negative symptoms of schizophrenia involve a syndrome of flattened affect and amotivation accompanied by emotional and social withdrawal. It has been suggested that this may reflected, at least in part, hypodopaminergic function in the prefrontal cortex [16]. Such a model would predict that increasing dopaminergic function in the prefrontal cortex may relieve negative symptoms. Classical antipsychotics have limited efficacy against negative symptoms. Given the inhibitory of serotonin on dopaminergic transmission, it has been hypothesized that drugs inhibiting serotonergic function may disinhibit dopaminergic transmission in the prefrontal cortex and, as a result, may improve negative symptoms. This hypothesis is supported by reports that clozapine, which is though to improve negative symptoms, induce an increased turnover of dopamine in the prefrontal cortex of rodents, an effect not seen with typical antipsychotics . Recent studies [17], suggest that this property of clozapine can be explained by its 5HT-2 antagonism. Both SSRIs and 5HT-2 antagonists may improve negative symptoms. Whoever, SSRIs may exert an effect on the depressive component of negative symptoms, while, the 5HT-2 antagonists may exert an effect on the extrapyramidal symptom component of negative symptoms. It has been hypothesized that 5HT-2 antagonistic action of clozapine, would lead to enhanced dopaminergic transmission in the prefrontal cortex, which in turn could ameliorate negative symptoms [12]. All these aspects on the role of serotonin - dopamine interaction raise the issue of using two drugs, one with specific 5HT-2 and another with specific D2 antagonism to obtain the benefits of the serotonin - dopamine interaction. Atypical antipsychotics like clozapine and risperidone may have an optimal balance of 5HT-2 and D2 affinities, which provides the benefits of serotonin - dopamine interaction [3].

ATYPICAL ANTIPSYCHOTICS

The distinction between classical and atypical antipsychotic drugs has attained considerable importance since a new generation of antipsychotic drugs with important advantages over the first generation of antipsychotic drugs (i.e. the classical antipsychotics, usually referred to as neuroleptics) has been introduced into clinical practice or is in an advanced stage of development. Ironicaly, the first studied atypical antipsychotic drug is not a new drug at all but an old one, clozapine. Not all investigators approve of the designation of a group of atypical antipsychotic drugs, preferring to describe all antipsychotic agents in terms of their currently perceived key pharmacological properties. Common to all definitions of atypical antipsychotics drugs is the ability to produce an antipsychotic action in most patients at doses that do not causes significant extrapyramidal side effects, such as parkinsonism and akathisia [3].

Clozapine

Clozapine was first tested in the 1960s in Europe . Its effectiveness as an antipsychotic without producing EPS was confirmed in early clinical trials. However it was observed to produce agranulocytosis at a range much higher ( 1 in 100) than that usually found with standard neuroleptic drugs, approximately 1 in 2000. This lead to the withdrawal of clozapine from the clinical use. However, some patients were permitted to use clozapine because they did not respond well to typical neuroleptics or expressed strong preference to clozapine because of its low EPS profile. This clinical experience with clozapine suggested that it differed from typical neuroleptics drugs in causing fewer EPS, had more diminished liability to cause tardive dyskinesia, it possibly had superior efficacy for some schizophrenics and that it not cause elevation of serum prolactin [3]. Kane et al [9] in 1988 reported the results of a double - blind six - week trial comparing clozapine with chlorpromazine in hospitalized neuroleptic - resistant patients. This study showed that clozapine was superior to chlorpromazine for alleviating both positive and negative symptoms. On the basis of this study, clozapine was approved for use in the USA and subsequently in other countries. There is also evidence that clozapine may be at least , or more, effective than other antipsychotics in a variety of conditions, such as treatment - resistant mood disorders, including : rapid cycling and dysphoric mania, psychotic depression and organic psychosis [18]. Clozapine has been found, also, to have modest effects to improve cognitive functions as attention, verbal fluency, recall memory and executive function [19]. Clozapine practice has been to use 200-600 mg/day in twice a-day dosage because the half-life of clozapine is 12-16 hr. There is no evidence for a therapeutic window and the tow major metabolites appear to be inactive. The major side effect of clozapine, which limits its use, is its significant risk of agranulocytosis. When the total WBC count falls below 3000/mm or the neutrophils count below 1500/mm, clozapine must be discontinued. Other side effects are : dose - related seizures or myoclonus, hypersalivation and weight gain [2].

Risperidone

Risperidone, like clozapine, is a potent 5HT-2A, 5HT-7, α -1, α -2 adrenergic, histamine H-1 and a relatevily weak (in comparison with its affinity for the 5HT-2 receptor) D-2 dopamine receptor antagonist. However its absolute affinity for the D2 receptor is similar to that of haloperidol (1 to 5 nM). It has low potency as an antagonist at D1 and D4 receptor. It should produce less EPS at effective antipsychotic doses than typical neuroleptics. Risperidone, unlike clozapine, stimulates prolactin secretion in man [3]. Risperidone, in doses 4 to 10 mg/day appears to be at least equivalent and possibly superior to haloperidol 10 to 20 mg/day in decreasing positive and negative symptoms. Some studies have reported risperidone to be superior to haloperidol in treating positive and negative symptoms in schizophrenia and to possibly have a faster onset of action [20]. In a recent SPECT study, [21] both risperidone and haloperidol produced D2 occupancy levels between approximately 60 and 90 % and parkinsonism was observed with routine clinical doses. In this study the author suggest that risperidone may be more similar to classical neuroleptics than previous experience would suggest. The most common side effects of risperidone are : insomnia, anxiety, agitation, sedation, dizziness, hypotension, weight gain and menstrual disturbunces.

Olanzapine

Olanzapine has a chemical structure similar to that of clozapine. It has high affinity for 5HT-2A, α 1 adrenergic and muscarinic receptors, and D2 affinity that is less than that of haloperidol but greater than that of clozapine. Olanzapine appears to be effective in reducing both positive and negative symptoms, with few EPS and minimal elevation of prolactin. It shares clozapine”s propensity for sedation and weight gain, but has not shown any tendency to produce agranulocytosis [22]. There are also evidences, [23] that olanzapine demonstrate greater efficacy in negative symptoms and in overall response rate as well as lower incidence of EPS, hyperprolactinemia and sexual dysfunction in comparison with risperidone.

Quetiapine

Like clozapine, it has high affinity to 5HT-2 receptors and lower D1 and D2 affinity. It also excibites H1 and α 1 adrenergic binding and moderate α 2 activity. It demonstrates selectivity for limbic rather (especially the mesolimbic A10 dopamine cells) than motor dopaminergic pathways. Clinically it appears to be effective in the treatment for both positive and negative symptoms and its propensity to produce EPS and to increase prolactin levels is low. Phase II and early III clinical studies confirm the preclinical findings that suggest quetiapine would be an effective antipsychotic agent with specific efficacy in the treatment of positive and negative symptoms [24].

Sertindole

Sertindole binds strongly to D2, 5HT-2A and α 1 adrenergic receptors. Clinically it improve both positive and negative symptoms of schizophrenia and its EPS profile is not appear different from that of placebo. Special care should be taken regarding the cardiovascular effects of sertindole. Postural hypotension and increase in the QT interval (in the ECG) are common side effects [2].

Zotepine

Zotepine, a dibenzothiepine tricyclic antipsychotic structurally similar to clozapine, is available in Japan since 1982 and have recently introduced in Germany. It has shown efficacy against positive and negative symptoms, with a marked atypical profile that is a low propensity to induce EPS and no reported tendency to cause tardive dyskinesia [25, 26].

Ziprasidone

Ziprasidone is a new antipsychotic in late-stage clinical development. It has the higher 5HT-2A / D2 binding affinity ratio (11, defined as 5HT-2A 1/Ki : D2 1/Ki). It is a potent 5HT-1A receptor agonist, a potent 5HT-1D and 5HT- 2C receptor antagonist and moderately inhibits 5HT and norepinephrine reuptake sites in vitro. It has negligible muscarinic activity and only modest affinity for H1 and α 1 receptors. The receptor binding profile of ziprasidone differentiates this compound from both standard neuroleptics and newer antipsychotics. Double-blind clinical trials indicate that ziprasidone 80-160 mg/day is well tolerated and effective in the treatment of positive, negative and depressive symptoms of schizophrenic and schizoaffective disorder [27] . DIFFERENCES BETWEEN ATYPICAL AND CLASSICAL ANTIPSYCHOTICS Biological evidences

Stockmeier et al [28] studied the in vitro potencies of 10 classical and 10 atypical antpsychotic drugs in occupying D2 and 5HT-2 receptors in rat brain. N-[3H] methyspiperone was chosen as the radioligand because it binds in vivo to 5HT-2 binding sites in the frontal cortex and to D2 binding sites in the striatum in mice, baboons and humans. The primary findings was that the group of classical antipsychotics drugs examined (from five different classes) can be distinguished from the group of atypical antipsychotic drugs that are clozapine - like on the basis of the atypical antipsychotic drugs having a relatively higher ratio of occupancy at 5HT-2 vs D2 receptors as measured in vivo. In addition, this group of atypical antipsychotic drugs was significantly less potent in vivo at D2 receptors on an absolute basis than the group of classical antipsychotic drugs. The atypical antipsychotic drugs were, also, slightly but significantly more potent in vivo in occupying D2 binding sites in the olfactory tubercle than in striatum consistent with the evidence that the atypical antipsychotic drugs, which produce a lower incidence of EPS, interfere less than classical antipsychotic drugs with dopaminergic function in the striatum. The finding that chlorpromazine and amoxapine resemble the atypical antipsychotic drugs in the occupancy of limbic vs striatal D2 receptors and relative occupancy of 5HT-2 vs D2 receptors indicate that some other factors may also be involved in the ability of atypical antipsychotic drugs to diminish psychosis without causing EPS, e.g. effects on dopamine release or other receptor subtypes. It has been postulated that a high 5HT-2 / D2 affinity ratio underprints the enhanced therapeutic efficacy, including efficacy in negative symptoms and low propensity for EPS observed with newer antipsychotics. Ziprasidone has the higher 5HT-2 / D2 binding affinity ratio (11), following by risperidone (6.9), clozapine (5.5), olanzapine (4.4), chloropromazine (0.3) and haloperidol (0.016) [27]. All these findings are in accordance with findings in PET studies where clozapine induce 20-67 % D2 receptor occupancy and the classical neuroleptics 70-90 % . Clozapine induce also high 5HT-2 receptor occupancy , >80%, even at low concentrations when the D2 receptor occupancy is only 20%. Many authors have claimed, as referred previously, that the atypical effects of clozapine are related to a combined effect on D2 and 5HT-2 receptors. Some other authors suggested that the mechanism of action of clozapine include involvement of the D1 receptor. The results confirm that clozapine induces a higher D1 receptor occupancy that do classical neuroleptics (0-44 %) and they finely hypothesized that a combined D1 and D2 receptor antagonism may have a synergistic effect and account for the atypicality of clozapine [11, 29, 30]. Recent investigations have focused on the D4 dopamine receptor as a potentially important site of action of clozapine [31]. Roth et al [32], however, discovered that although several antipsychotic drugs had high affinities for the D4 receptor, neither the D4 affinity per se, nor D2 / D4 or the 5HT-2A / D4 ratios reliably distinguish between classical and atypical drugs.

Clinical evidences

There are strong clinical evidences that the atypical antipsychotics present the following clinical characteristics that differentiate them from the classical antipsychotics : a. They are associated with less risk of neurological side effects (parkinsonism, acute dystonia, tardive dyskinesia, malignant neuroleptic syndrome, akathesia, sedation, and increased prolactin secretion). b.Most of them seem to be more potent in decreasing negative symptoms (anhedonia, affective flattening, avolition etc). c.At least clozapine, seem to be more potent in decreasing positive symptoms (delusions, hallucinations etc). It provides the possibility of significant help for at least 60% patients with schizophrenia who fail to respond adequately to classical neuroleptics. d.Clozapine has been found to have modest effects to improve cognitive functions (attention, verbal fluency, recall memory etc). It remains to determine if other atypical antipsychotic drugs also improve cognitive function. e.At least clozapine and ziprasidone, seem to be more effective in decreasing depressive symptoms in schizophrenic, schizoaffective and major depressive with psychotic features patients.

Future prospects

There are now numerous drugs in advanced stages of clinical testing as potential atypical antipsychotic drugs. The major focus of drugs in development is on 5HT-2 / D2 antagonists , the clozapine like drugs, that have been already analyzed. The second group is the 5HT-2A antagonists . Amperozide and MDL100937 are potent 5HT-2A antagonists but have no apparent D2 blocking effects. Ritanserine have already reported to be effective in treating positive and negative symptoms in schizophrenia. These results suggest that 5HT-2A antagonism by itself may be a sufficient means of treating some types of schizophrenia [3]. The third group is the 5HT-3 antagonists . There is a considerable evidence that 5HT-3 antagonists may be effective antipsychotic drugs, but clinical evidence is lacking to support this strategy. Fourth, the D1 receptor blockade has been thought to be a potential way to achieve an antipsychotic effect with low EPS, because has long been known that D1 modulate D2 receptor function in complex ways. There are various D1 receptor antagonists in clinical development (e.g. SCH 39166, NO-01-0687, DOD 647). Fifth, the hypothesis of administering dopamine autoreceptor agonists to suppress the synthesis and release of dopamine is being studied. The initial clinical studies with these drugs suggest a weak effect on negative symptoms [33]. Sixth, the sigma receptor has been implicated in psychosis, but this has been disputed. A new sigma antagonist with 5HT-2 receptor blocking properties, DUP 734, appears to be of particular interest based upon its ability to block the behavioral effects of phencyclidine [34]. Finally, more recent theories, have suggested that primary disturbances in glutamatergic functioning may be aetiological in schizophrenia. This concept is supported by a variety of findings in schizophrenia including reduced glutamate concentrations and abnormalities in glutamate receptor density, function and metabolism [1]. The only therapeutic approach applicable to date for counteracting the hypothesized reduction in glutamergic function targets the strychnine - insensitive glycine recognition site of the NMDA receptor complex. Glycine, acting as a co-agonist at this site, can potentiate NMDA receptor - mediated neurotransmission and, in coadministration with antipsychotics, seems to reduce further the negative symptoms of schizophrenic patients [35].

RAPE

Epidemiology

Russell's (1984) wide research in random samples of San Francisco women is regarded by now the most thorough research in relation to the measuring of undesired sexual experiences. The percentage of 24% which is extracted by this survey keeps up with the 27.5% of Koss et al (1987) which resulted after a sample survey on American female students who reported rape or attempt of rape from the age of 14. Gavey's (1991) research in New Zealand resulted to a similar percentage (25.3%) of women who reported rape or attempt of rape. As Koss (1992) marks, women have four times more chances to be raped by a familiar person rather than a stranger. This remark agrees with Gavey's (1991) results, which indicate that two thirds of reported undesired sexual experiences were committed within a type of heterosexual relationship, while the percentage rises up to 80% if familiar persons, ex-husbands, ex-friends and lovers are included. According to the International Statistics on rape from the UN, one in six women has been raped. Nearly one in eight of Black women has suffered racist sexual assault. Two women a week are murdered by their partner or ex-partner, while 98% of domestic violence is not reported to the police.

Theories on sexual aggressiveness and rape

Psychodynamic Theory

Psychodynamic researchers always included in their theories the notions of castration stress and oedipodean opposition. These theories support that various emotions of fear and sexual or personal inadequacy, sexual and personal, along with the possible existence of unrecognized homosexual tendencies, interact with aggressiveness and are directed towards the victim as a substitute for mother, resulting in sexual abuse (Freud, 1905/1953, Fenichel, 1945, Rada, 1978, Groth et al, 1977).

Behaviorist Theory

The behaviorist model of “emotional state augmentation” suggests that non sexual emotional situations act complicatedly with sexual stimulation, in order to induce sexual response. This is a possible mechanism which is implicated in the positive (love) and the negative (hate) interactions of a relationship. The model of “ state disinhibition of arousal” suggests that the non consensus pain and suffocation on behalf of the victim, as well as the emotions of fear, cause the inhibition of rape stimulation in most men. The mechanism in question is regulated by the ability of a person to empathize (Malamuth & Check, 1983). Indications of such a case come from phallometry, which shows that the proportion of stimulation during scenes of rape, in opposition to scenes of sexual intercourse by consent, is higher to rapists and is related to the number of the victims and the extend of violence (Abel et al, 1977). The inhibition of stimulation during scenes of rape is for some reason absent in rapists. The cause or the circumstances, under which this is due to happen, relate to the general behavior of the environment. Such examples include situations where the victim is attributed with provocative outfit or situations that evoke anger to the rapist.

Socio-cognitive Theory

The bibliography on sexual offenders describes the prejudiced way of processing the information in almost every step of the chain of perpetration (Marshall & Barberee, 1989). The expectations or the beliefs of the sexual offenders affect the process of the information related to sexuality (Stermac & Segal, 1989). For example, rapists regard the way their victims dress as a “challenge” and they have difficulty in realizing the situation on behalf of their victims. Similarly, during perpetration the rapist conceives the passivity or the terrified consent of women as desire and pleasure of the rape. The more confused the behavior of the victim is, the easier is for the rapist to misinterpret it. Mallamuth & Brown (1994) defined the following dysfunctional mechanisms concerning the insights or the beliefs of the sexually aggressive men: 1) Hyper-perception of hostility/seductiveness, meaning that aggressive men have difficulty in discriminating between friendliness and provocativeness and between claim and animosity. 2) Negative blindness, meaning that sexually aggressive men are incompetent to realize the negative female signs. 3) Suspicious attitude, meaning that the sexual aggressive men regard the female sexual behavior and its relations as unreliable. Such a prejudiced information process creates high levels of distrustfulness and animosity towards women, and eventually sexual violence.

Feminist Theory

One of the main feminist theories was that of S. Brownmiller, who in 1975, with her book “Against Our Will”, laid the foundations for the feminist view of rape. Also, Burts' feminist theory (1980) for rape described the way social beliefs reinforce sexual aggressiveness. They suggested that the standard views for the role of the sex, the contradictory sexual beliefs, as well as the acceptance of interpersonal violence, are important factors which stand between the culture of society and sexual aggressiveness. Feminist theory regard rape as a pseudo-sexual act induced by the sociopolitical domination of men. It was cited that not only rape but also the fear of a potential rape serves a mechanism of social control (Brownmiller 1975, Riger & Gordon 1981). During the ‘70s rape was a major issue for the feminist movement, a fact which at least partially was attributed to the belief that this form of violence was due to the change of roles which women gradually experienced (Donat & D' Emilio, 1992).

Socio-biological views

In the socio-biological theory of Ellis (1989, 1991), the biological variables have evolutionary meaning. According to this theory, men in contradiction with women, tend to maximize their capacity to mate by the sexual intercourse with many different partners. Ellis' theory clearly suggests an almost sexual incitement in rape, a fact which contradicts the feminist views and those on social learning. He also suggests that the non sexual dimensions of the rapists' behavior, such as the aggressive and dominative behavior, should be regarded as a strategy rather than a target. In addition, Ellis attributed testosterone with the leading role that, according to his estimations, affects not only the tension of the sexual urge, but also the sensitivity towards the thread of punishment and the ability to understand the pain of others (empathy).

Biological Theories

Many parameters of a normal adult man's sexual behavior seem to depend on androgens. The low levels of testosterone are related to an important decrease of sexual fantasies, sexual stimulation and desire, automatic night erection, ejaculations and sexual activity. In addition, certain sexual activities such as masturbation and orgasm, temporarily increases testosterone levels, while in contrast, the stressful incidents of life decrease testosterone levels (Christiansen, 1998). Studies show that in both men and women, aggressive behavior is related to the circulated androgens, and this fact seems to apply mostly in adolescents and children than adult men. Studies in prisoners also showed that prisoners with a record of violent crimes had higher testosterone levels, in relation to those with no such record, while research on the relation between androgens and sexual aggressiveness showed controversial results (Dabbs et al, 1987, Olweus et al, 1988, Giotakos et al 2003, 2004). Several researches have described the more or less successful confrontation of sexual aggressiveness using the anti-androgens acetic methoxyprogesterone και acetic cyproterone . The first, effecting directly to the testosterone, inhibits the excretion of gonadotropines, and the second competes directly with the effect of testosterone into the receptor of the target organ, resulting to the reduction of the testosterone levels. In addition, the suppression of the hypothalamic-pituitary-gonadal axis by a GnRH (Gonadotropine Releasing Hormone) agonist seemed to reduce at a great extend both the testosterone levels and the sexually aggressive behaviors (Rosler & Witztum 1998).

Psycho-social features of sexual offenders

Family history

A number of family factors which intervene significantly in the development of the sexual aggressiveness have been identified. Interrelating factors, such as bad and distant relationships with the parents, unstable or neglectful care, loss of a parent due to death, separation or divorce and high frequency of physical and sexual abuse, are the factors that characterize the early childhood experiences of many sexual offenders (Prentky et al., 1989, Ryan &Lane, 1991, Seghorn et al., 1987).

Education record

Even though their educational development varies, rapists tend to leave school. Obviously, cognitive capacities affect the course of the treatment. For that reason, the estimation should include the educational record, the general cognitive level and the existence of learning difficulties. The achievement of educational goals and good behavior in school give useful information concerning the cognitive and psychological abilities. For example, difficulties in attending the lessons, impulsiveness, lack of goals, low self esteem and persistence can be detected. These factors have obvious effect on the development of the therapeutic procedure of the offender's sexual behavior and can suggest the need for additional educational intervention (Bard et al, 1987).

Work record

The existence of a stable work record tends to protect from the development of criminal behavior. Indeed, rapists tend to have unstable work record in unskilled professions. It is thus useful that the work record is evaluated focusing in stability, type of work, level of capacity and responsibility and the overall attitude towards the work. These factors might relate to psychological characteristics such as persistence, capacity of tolerating defeat and the ability to plan and achieve goals. The information provided by the work record could also indicate the need for special interventions aiming in raising the future ability for work (Bartol, 1991, Bard et al., 1987).

Social record

People who have a record of deranged attachment with those who have raised them are more likely to present dysfunctional relationships in other sectors as well (Hazan & Shaver, 1994). Baring in mind the aforementioned deranged family relationships the fact that rapists have a problematic social record is not surprising. For example, low levels of emotional interference with their colleagues has been reported (Blaske et al., 1989), while a 85% had few, if no friends at all during adolescence (Tingle et al. 1986). Thus, recognizing the significance of the early childhood experiences in the future development of social stress, the thorough investigation of the social record is regarded necessary. The evaluation should include quality, stability and duration of friendly relationships, nature and extend of social isolation, the form of interpersonal relationships, the difficulties that might existed during early relationships and the way a person deals with sexual relationships. The detection of potential deficiencies in a rapists' social life is crucial for the planning of the treatment. Knight & Prentky (1987) emphasizing on the study of social relationship development factors and type of offence, concluded that rapists who present sadistic tends, compared with other types of rapists, have more often been assaulted themselves and had poorer social life, low levels of heterosexual dependability and more unstable interpersonal relationships.

Sexual record

A series of common features in the sexual record of rapists has been identified. Men who present high levels of sexual aggressiveness seem to have had early and often sexual experiences (Koss, 1989) more loose beliefs on sexuality in general (Marshall, 1989), and also presented indications of increased morbidity related to paraphilia (Freund, 1990, Marshall et al, 1991), as well as increased occupation with pornography (Carter et al, 1987). It is commonly accepted that a significant number of rapists have been sexually assaulted during their childhood or have witnessed deviating sexual activity (Dhawan & Marshall, 1996). But not all the assaulted during childhood present sexual aggressiveness. This fact indicates the existence of other factors which intervene in the course of development of sexual activity, such as the desire to humiliate the victim and the lack of empathy (Finkelhor, 1984).

Sexual relationships

Several researchers observed that sexual offenders are socially isolated and had only a few intimate sexual relationships (Fagan & Wexler, 1988, Marshall 1989, Tingle et al., 1986). In addition, the sexual offenders who had many relationships describe them as superficial ( Marshall , 1989). The common element among sexual offenders is the failure to contract an intimate sexual relationship, which leads them to isolation (Tingle et al., 1986). After comparing separately non sexual offenders and the general population, sexual offenders presented greater difficulties in developing a sexual relationship, as well as significantly higher levels of feeling isolated. Similar were the results among prisoners convicted for sexual offenses, while especially the prisoners charged with incest, compared separately with rapists and non sexual offenders, present higher levels of fear for developing an intimate sexual relationship, while rapists compared with pedophiles present low desire for an intimate relationship with other men and members of their family (Bumby & Marshall, 1994).

Psychiatric record

The existence of mental disorders is often in rapists. According to a research , one third of a sample of rapists was diagnosed with depression, while two thirds were diagnosed with overuse or dependability from alcohol (Hilbrand et al., 1990). Another research found high frequency of stress disorders (Dewhurst et al., 1992), while another one (Seghorn et al., 1987) found 7% schizophrenia, 2% schizo-emotional disorder, 3% major depression and 6% organic psycho syndrome. Examining the disorders of Axis II (Personality Disorders), Seghorn et al (1987) observed that almost one third of the sample presented personality disorder, while other researchers found higher levels, even up to 90% (Berner et al., 1992, Serin et al, 1994, Stermac & Quinsey, 1986). The recent models of sexual aggressiveness focus mostly on the antisocial personality characteristics and less on other features (Marshall & Barbaree, 1990). Additionally, drug abuse is usual in rapists. Particularly, alcohol use seems to very often precede a rape. Alcohol use or abuse increases significantly violence levels, as well as the possibility of an occasional rather than a planned rape .At least half of the prisoners for rape were found to have consumed excessive quantity of alcohol just before the rape (Seto & Barbaree, 1995), while according to the results the use of alcohol was related to sexual aggressiveness (Abbey, 1991, Richardson & Hammock 1991).

Commorbidity with paraphilias

Exhibitionism was always related to rape (Paitich et al., 1977). Gebhard et al (1965) suggested that 1 in 10 exhibitionists has seriously thought or attempted rape. Abel' s et al (1986) research found that out of 126 rapists who were examined, 44% had sexually assaulted girls outside the family circle, while 14% had additionally assaulted boys outside the family circle. However, several significant differences between rapists and pedophiles, related to the characteristics of the adult and the former development phase have been found. Rapists, compared with pedophiles, tend to be younger, have graduated from high school, impose themselves (aggressive) rather than being imposed to (passive), have been married or connected with a woman for a satisfactory period, and tend to rarely present mental deficiency or some organic brain syndrome. During the development stages, rapists compared to pedophiles, tend to come from non divorced parents, do not have relatives with psychiatric record, have half possibilities to have experienced sexual assault, have not presented significant health problems, but have abused animals and have demonstrated problematic behavior in school (Bard et al., 1987).

Commorbidity with non-sexual aggressivity

People who had been convicted for rape had often been convicted for non sexual crimes as well, and this fact seems to apply also for adolescent rapists (Epps, 1991). It was also found that half of the rapists had been convicted at the same time for other non sexual crimes, while almost all of them had committed at least one non sexual attack. However, it has not been defined whether these facts characterize all rapists, including the occasional ones (Stermac & Quinsey, 1986).

Phallometry

The discrimination between rapists and non rapists by the method of phallometry has changed a lot during the last years. At the end of the 70's and the beginning of the 80's, bibliography clearly stated that the models of the rapists' sexual stimulation were different than those of the non rapists (Abel et al., 1977, Barbaree et al, 1979, Quinsey et al., 1984). It was also observed that rapists react similarly in case of non sexual violence towards women and it was assumed that the criteria of violence are the connective link. However, more recent research showed several similarities between rapists and non rapists since both groups demonstrate low levels of sexual stimulation in scenes of rape, compared to the stimulants which include consensus sexual intercourse (Blader & Marshall, 1989, Murphy et al,. 1986).

Sexual offenders' treatment

Treatment programs

Examples of integrated programs on sexual offenders come from USA , Canada , Australia and England ( Marshall et al, 1998) . In general, the treatment interventions of sexual offenders are distinguished in those performed in prisons and those performed within the community, in other words on persons who are under surveillance or probation or have just been released from prison. The therapeutic programs for confronting sexual crime prisoners are usually held in the form of group therapy. The primary goals are: 1) Settlement of minimization issues and resumption of responsibility, 2) definition of the circle or the procedure which results to crime, 3) definition and supervision of individual therapeutic goals, 4) learning the prevention methods and 5) help to embody therapeutic material from other groups. The group also acquires training in basic social skills, such as communication skills, empathy towards the victim, anger management, stress management, sexual hygiene etc. Each member of the group also acquires interpersonal therapy, mainly occupied with behavior, fears or individual procedure of depended sexual stimulation. In the end of the therapy it is expected that the person under cure will have acknowledged the factors which contribute to the procedure of the sexual crime, will be capable of detecting the situations which might increase the danger of relapse and will have acquired skills allowing the avoidance of high risk situations. It is recommended that his therapeutic intervention will be continued even after the release from prison. It is believed that in order to achieve satisfactory results the programs should last at least 2 years. In the community programs, which are run by the Probation Services, participate sexual offenders under surveillance or probation. These programs, as the aforementioned ones, use as basic therapeutic hubs the reduction of denial and the enforcement of the ability to resume responsibility, the incr ease of self-criticism ability and the enforcement of empathy towards the victim. Equivalent cognitive and behavioral techniques are also applied. According to the results, almost half of the participants after 54 hours of therapy showed a decrease in the parameters of cognitive perversion, empathy towards the victim and the sexual compulsivity on levels equivalent to those of non sexual offences ( Marshall , 1998). Alongside the psychotherapeutic forms of approach, other therapeutic methods have been tested and aim mainly to the reduction of sexual aggressiveness. Surgical confrontation, neuroleptics , and estrogens have been dispensed with, due to side effects. The antidepressants, especially the specific serotonin reuptake inhibitors (SSRIs), had satisfactory effects. Hormone therapies with anti-androgens and Gonadotropine Releasing Hormone (GnRH) agonists also had a satisfactory outcome in the reduction of sexual aggressiveness (Rosler & Witztum, 1998, Kafka, 1997).