An Integrative Model and Dynamic Nosology Of

Psychiatria Danubina, 2019; Vol. 31, No. 1, pp 2-17 https://doi.org/10.24869/psyd.2019.2 Review © Medicinska naklada - Zagreb, Croatia

AN INTEGRATIVE MODEL AND DYNAMIC NOSOLOGY OF PERSONALITY DISORDER: PART 2: SYMPTOM-BASED PHARMACOTHERAPY Dragan Svrakic1, Mirjana Divac-Jovanovic2 & Naazia Azhar1 1Department of Psychiatry, VA medical center St Louis, Washington University School of Medicine, St Louis, MO, USA 2Department of Psychology, Faculty for Media and Communication, Singidunum University, Belgrade, Serbia

received: 28.12.2018; revised: 15.2.2019; accepted: 26.2.2019 SUMMARY This paper presents an integrative model of personality and personality disorder which incorporates psychoanalytic concepts with modern neuroscience. In addition, a dynamic, personalized, and context - and time-sensitive diagnosis of personality disorder is introduced. The authors cogently argue that all clinical variants of personality disorder share the same common deficit: fragmented basic units of experience at the nonconscious core of the mind (aka “partial object relations”). The fragmentation propagates through mental faculties (thought, motivation, emotion), as they self-organize into subsystems of personality, e.g., one’s sense of self, identity, character, moral values, rendering them polarized into extreme and thus adaptively suboptimal. The syndrome of personality disorder arises as a nonconscious compensatory maneuver of the fragmented mind to organize itself through a defensive but unrealistic self-image (e.g., narcissistic, schizoid, antisocial, etc.), giving rise to a host of unique symptoms. Symptomatic pharmacotherapy of personality disorder is best organized around four empirically derived domains of symptoms, shared by all variants to a variable degree: i) mood and anxiety dysregulation; ii) impulsivity, aggression, and behavior dyscontrol; iii) emotional disinterest and detachment; and iv) cognitive distortions and brief reactive psychoses. Pharmacotherapy targeting the above domains is nonspecific, as medications affect multiple domains simultaneously. Modest empirical evidence and considerable clinical benefits continue to support the use of medications in the overall symptomatic treatment of personality disorder.

Key words: personality disorder - pharmacotherapy - integrative model - temperament - character

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INTRODUCTION AN INTEGRATED, PERSONALIZED, AND DYNAMIC CONCEPT OF The most important goal of this paper is to challenge PERSONALITY DISORDER the therapeutic nihilism which surrounds the syndrome of personality disorder. These individuals are widely The human mind is best conceptualized as a pro- considered “untreatable”, even by many mental health gressively differentiated brain’s adaptive agency that professionals. We argue that they can be effectively mediates the brain’s dynamic and interactive commu- treated, but the success requires expertise and time: a nication with internal and external environments (Proust precise1 diagnosis (not only of clinical symptoms but 2 2009). This fundamental adaptive function of the mind also of the underlying organization of the mind) , indi- is subserved by mental faculties of thought, emotion, vidualized treatment planning (combining expert phar- and motivation, also called “mental trilogy”. As a self- macotherapy and in-depth psychotherapy), a patient organizing complex adaptive system, the mind develops determined to change (preferably one who trusts psy- through punctuated homeostasis, with periods of chological mechanisms to achieve change), and an relative stability (maintained by homeostasis) followed expert clinician with a genuine interest in this type of by rather abrupt transitions (homeostatic optimization) psychopathology, who is skilled in both psychotherapy towards increasingly complex organization and func- and pharmacotherapy or, alternatively, a close collabo- tioning (called development) (Svrakic et al. 1996). ration between an expert psychotherapist and a skilled These abrupt transitions occur whenever the mind, psychopharmacologist. configured to function optimally in a given set of conditions, becomes suboptimal to meet increasingly complex or different adaptive tasks. For illustration, temperament, which is the main and perfectly adequate

1 avenue to communicate needs to the environment du- Irresponsible diagnosing of every loud, belligerent, or ring the first year of life, becomes adaptively subopti- manipulative individual as personality disorder has in part created the untreatability myth of the bona fide cases mal in the context of subsequent more complex interactions. At this point, an adaptively fitter subsystem, the 2 Mind, mental (mens = Latin for mind), and personality are equivalent concepts: personality is the unique configuration of sense of self, abruptly self-organizes within the mind at the mind in a given individual, as discussed in the text around 2-3 years of life.

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The neuroscience of psychoanalysis: a primer units of experience can be thought of as the “core” of the mind. How exactly the subsystems of the mind come Under normal circumstances, the early mind is pola- to existence is not known. A straightforward speculation rized because negative (frustrating) and positive (plea- is that during the progressive differentiation of the surable) experiences are engramized by anatomically mind, reflecting self-organizing multidirectional optimi- separate subcortical regions. However, the maturing zation processes to meet the increasing adaptive de- general network of cognition3 eventually becomes 4 mands before it, the brain’s functional networks invol- capable to functionally bridge the separated extremes ved in thought, emotion, and motivation self-organize into a realistic, balanced understanding of self and into semi-stable configurations which we refer to as the others as sometimes “bad” but predominantly “good” subsystems of the mind: contextualized temperament, (“whole object relations”). We refer to object relations the sense of self, character, moral standards (both ad- as “elementary particles of the mind”, because each vancing social adaptation), and identity (the assuring encompasses a memorized perception of an object, the "who" of "me" which provides the sense of consistency related self-reflection, and the connecting affect. This and thus enables planning for the future). Each of these functional union is not divisible to lower order units of subsystems emerges canonically at a specific developmental experience, only to first order sensory percepts mental phase and each provides a specific adaptive and subcortical affects. Others have referred to object function to the system of the mind as a whole. relations as the “basic units of all experience” formed Observation of infants and children provides the from fantasy and real early interactions (Auchincloss & timeline for personality (mind) development. The non- Samberg 2012). conscious self-HORs, based on body sensations and Based on LeDoux and Brown (2017) we postulate rudimentary self-reflections within nonconscious wor- that object relations, whether partial or whole, operate king memory, distinguish self (“I”) from other (“not I”) within nonconscious working memory. To elaborate, all around 6 months of age. It is a mental state “but in an sensory events, factual- and autobiographical memories, extremely thin sense” (LeDoux & Brown 2017) insofar and their respective affects are first order represented in as it does not invoke self- awareness. From here, the secondary sensory cortical areas, or engramized in the nonconscious self-HORs are re-represented by cognitive medial temporal lobe and the amygdala, respectively. networks (HOR of HOR or HOROR) which makes From here, they are “pulled” into nonconscious working them accessible by passive noticing as “phenomenally memory by the general network of cognition as higher conscious” sense of self (“me” and “mine”) around 2-3 order-representations (HOR) but are still nonconscious years of age. Phenomenal consciousness is best des- (nonconscious HOR of first order processing) (LeDoux cribed as “knowing how it feels”, or as “what is it like” & Brown 2107). From nonconscious working memory, 5 to have a first person experience (the taste of straw- these basic units inform the development of mental berries, the feeling of safety with the mother around, faculties (thought, emotion, and motivation), and thus etc.) (LeDoux & Brown 2017). Such passive experience fundamentally influence their nature (balanced in nor- is not accessible by active scrutinizing (introspection). mal development, polarized into extremes in personality For active introspection, another cognitive re-repre- disorder). The described sequence whereby sensory sentation (HOR of HOROR) is needed, for which cogni- events and affects are first higher order represented into tive networks become capable around 3-5 years of age, nonconscious working memory is a necessary step paving the way for the emergence of the sense of self as before cognitive networks can process them into being intentional and purposeful (“me and my intentions”) conscious. Thus, the nonconscious working memory which is actively accessible by introspection (aka “self- harboring nonconscious affective-cognitive elementary awareness” or “autonoetic consciousness”)6. Around the same time (cca. 5 years of age), maturing cognitive networks enable the emergence of theory of mind of others, 3 General network of cognition (GNC) includes circuits spread capacity for mentalization (McAdams 2017) and capa- across frontal and parietal areas: anterior cingulate cortex, city for autobiographical memory. The latter underlies lateral and medial orbital frontal cortex, dorsolateral, the sense of identity, which allows the experience of dorsomedial, ventrolateral, and ventromedial prefrontal cortex (PFCx). GNC is implicated in the development of cognitive continuity in time and space (“me, my past-, present-, processes of attention, working memory, and metacognition, and- future”) (reviewed in detail in Svrakic & Divac- which are important in the development of conscious Jovanovic 2018). The exact mechanism of cognitive re- experiences (for details see LeDoux & Brown 2017). presentations and re-representations is not known. What 4 The merging into whole object relations is not structural, but is known is that they are functional (not structural) a function of working memory, most likely nonconscious (emerging functions by the work of GNC), but in all working memory. likelihood involve some kind of rapid and neuro- 5 Serve as the rudiments upon which more complex thought, plasticity. Thus the subsystems of the mind are semi- emotion, and motivation are built. They are integrated into stable. these mental faculties and thus and thus cannot be conscious themselves, only indirectly recognized by the effects of their operations (e.g., mature vs extremized interpersonal reltions or 6 LeDoux & Brown (2017) provide an excellent discussion on self-image). the subject.

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The postulated existence of nonconscious working represents a shared impairment, a common denominator memory by cognitive neuroscience opens the door to cutting across all clinical variants of personality dis- reconcile psychoanalytic observations by M. Klein (the order (Divac-Jovanovic et al. 1993). The syndrome founder of object relations theory) with modern neuro- arises as a homeostatic maneuver of the early mind to science. As discussed, operating within nonconscious compensate for its fragmentation through uncontested working memory, internalized object relations funda- (omnipotent, wishful) defensive fantasy, the latter, by mentally inform mental development. Because these core brute force, unifies the fragments into a fantasized early experiences are highly personal, personality arises defensive ideal. This nonconscious strategy gives rise to as a unique configuration of the mind in a given indivi- a highly unrealistic yet a more stable self-image that dual, a concept supported by functional neuroimaging evades disintegration but further pathologizes perso- (Gratton et al. 2018). Incidentally, defense mechanisms, nality by funnelling it into deviance. The latter varies we believe, operate within the noncomscious working with clinical variants of personality disorder, each with memory as a homeostatic function of the mind. unique maladaptive behaviors which express the corresponding deviant self-image, e.g., antisocial, schizoid, Developmental homeostasis narcissistic, histrionic, paranoid, negativistic dependent, of personality disorder and anankastic, although mixed presentations are the most frequent. Such an adaptively suboptimal perso- Personality disorder follows the same developmental nality continues to vitally need sources of organization, path as normal personality would, but here in the con- both internally (through fantasy and exaggeration) and text of heritably excessive temperament traits (“trait vul- interpersonally (through a continual need for self- nerabilities”) and/or adverse environments (“bad-enough objects). The latter are expected, frequently demanded, environments”). These overwhelming risk factors, singly to define and maintain the unrealistic self-image of the or in concert, interfere with the maturation of prefrontal patient, hence the frequent interpersonal conflicts. functional networks and disrupt normal mental develop- Personality disorder is not a static, lifelong diagnosis ment, both well documented aberrances in personality as is commonly believed. The average short-term test– disorder. As a result, polarized “either-or” elementary retest reliabilities are 0.54 for specific subtypes and 0.56 units of the mind, aka “partial object relations” patho- for any personality disorder, even with structured logically persist at the nonconscious core of the mind. interviewing (McGlashan et al. 2005). Longer term test– The persisting polarization protects the few positive retest reliabilities are found to be 0.51 for any perso- experiences which are in minority, and thus endangered nality disorder and 0.34 for specific subtypes, which, to be annihilated, but are vital for mind development. It together with significant diagnostic change over as little is unclear whether the continuing splitting reflects a as six months, indicate a diagnostic reversibility of the nonconscious defense mechanism (psychoanalytic inter- syndrome (reviewed in APA 2012). However, perso- pretation) or stress-related hypofunctional PFCx (neuro- 7 nality disorder is not quite a state condition as well, but science interpretation) , or perhaps the former is simply is captured by the concept of semi-stability: it fluctuates a function of the latter. However, as a phylogenetic with changing internal or external conditions, both given, a mind and its subsystems have to develop in a stabilizing and destabilizing. Incidentally, the same is human being, and this even with defective building true of normal personality. Such semi-stability calls components. This is known as “developmental homeo- for a dynamic nosology of personality and personality stasis”, a biological process in which all animals deve- disorder. In contrast to current static classifications lop more or less normally within a range, despite some (DSM, ICD) and other popular concepts of personality polymorphic genes and less than perfect environments. pathology (Kernberg, Millon) we have developed a In personality disorder, mental development is informed dynamic and personalized diagnostic approach within by fragmented elementary particles and this renders a 3D diagnostic space in which each individual is personality adaptively suboptimal. We have empirically 8 uniquely positioned: two intersecting dimensions, one shown that borderline (i.e., fragmented) personality vertical, representing the person's qualitative level of level of mind integration or, as we call it, “level of

7 mental functioning” (the "how" of personality), and one Stress affects PFCx network development and topology in horizontal, representing his or her maladaptive behavior two ways: mild stress drives random brain networks toward scale- free, crash- resistant connectivity, whereas severe and style (the "what" of personality) are cross matched in persistent stress may interfere with the development of scale- the given time and context. Such dynamic nosology is free connectivity, even fracture the already established ones inherently sensitive to fluctuations in mental functioning (Zorumski & Rubin 2011). Sych hypofrontality has been over time and context, and gives the clinician precise documented in personality disorder. milestones for monitoring progress in therapy. 8 We advocate that the term “borderline” be replaced with the term “fragmented” personality, as the latter highlights intrapsychic fragmentation as the essence of personality disorder. The term “borderline” has been overused and (most clinicians), or to a separate category of personality misused to the point of confusion, as a type of personality disorder (DSM), the last two concepts plagued by stigma and organization (Kernberg), to denote any “difficult” patient therapeutic nihilism.

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TREATMENT OF PERSONALITY individual prepared in psychotherapy, may induce pro- DISORDER: TOP-DOWN found and lasting new insights, increased empathy, and AND BOTTOM-UP advanced sense of well-being. These positive changes are especially strong in subjects who reported an initial Both brain and mind aberrances characterize perso- experience of ego dissolution, i.e., that their sense of nality disorder: the former refer to hypofunctional cog- being a self or ‘I’ distinct from the rest of the world has nitive networks and hyper-reactive subcortical affects, diminished or altogether dissolved, as well as in the the latter to persisting primitive defense mechanisms subjects who were listening to music during the LSD and polarized object relations (reviewed in Svrakic & administration (hence, some have called the process as Divac-Jovanovic 2018, Kernberg 2015). In such patho- “finding the self by losing the self”). The changes are logical triad of hypofrontality, hyper subcorticality, and believed to be related to a resetting of functional cortical polarized mind, the components perpetuate each other in networks, much as the effects of in-depth psycho- a vicious cycle. As both cortical and subcortical pro- therapy. Routine clinical use of psychedelics needs cesses contribute to personality disorder, the treatment further systematic testing. What appears certain at this can approach the problem from two directions: i) top- point is that candidates for psychedelic pharmaco- down approach, which aims to improve cognitive con- therapy have to be prepared with multiple sessions of trol of heightened subcortical reactivity, or ii) bottom-up preparatory psychotherapy. approach, which aims to balance the impact of subcor- The bottom-up approach which aims to correct the tical affects on the mind as a whole. The two approa- over-influence subcortical affects on cognition and ches inevitably engage in a positive feedback whereby behavior historically has been the domain of pharmaco- improved subcortical affects facilitate self-organization therapy. Such heightened affect reactivity can be treated of more mature prefrontal networks and more effective within the theoretical context of heritably excessive cognitive (executive) functioning and vice versa. At this temperament traits, which not only act as risk factors or point, the healing of the brain/mind is not limited to “trait vulnerabilities” for personality disorder but also treatment sessions but continues through interactive continue to perpetuate the core psychopathology of experiences in non-supervised real-life situations, e.g., fragmentation. Thus, pharmacotherapy of excessive within a relationship with an unconditionally loving ma- temperament is bona fide “mechanism-based” (Svrakic ture partner, a rare but fortunate milieu for the fragmen- et al. in prep.). Pharmacotherapy can also aim to correct ted partner. clinical symptoms of personality disorder arranged into Improvement of the cognitive top-down control, pre- domains by co-occurrence. Here, we focus on the sumably reflecting maturation of prefrontal networks, symptom-domain based pharmacotherapy, which is the has been thus far the domain of psychotherapy. As dis- standard of care at the moment. Both mechanism-based cussed in part I of this paper, the most effective psycho- and symptom-based improvement in disruptive affects therapy is psychodynamic or psychodynamically orien- and behaviors are expected to facilitate one’s capacity ted, as these provide the best fit between the healing for engage in psychotherapy, although via funda- ingredient of therapy (i.e., corrective emotional expe- mentally different impacts, as discussed later. What is rience) and the postulated core impairment of perso- explicit in our concept of personality disorder is that nality disorder (i.e., polarized object relations) (review pharmacotherapy, whether mechanism-based or symp- in Svrakic & Divac-Jovanovic 2018). The following tom-domain based, is unlikely to be effective unless point is noteworthy: we understand the patient through combined with psychotherapy, i.e., that a combined top- transference and countertransference but heal him or her down and bottom-up approaches provide maximal ef- through the therapeutic relationship, as the latter fectiveness. Of note, mechanism-based and symptom- provides corrective emotional experience, akin to “re- based pharmacotherapies occasionally overlap (Svrakic parenting”, which recreates the natural milieu for mind et al. in prep.). development. More recently, there has been a renewed interest in pharmacological modulation of cortical SYMPTOMS OF PERSONALITY functions, using agents classified as psychedelics9, like DISORDER REFLECT WIDESPREAD empathogen-entactogens serotonin releasers (LSD, NEURAL AND MENTAL DEFICIENCIES psilocybin) or dissociatives related to glutamatergic mechanisms (like ketamine). Several reputable resear- Phenomenology and symptoms of personality dis- chers are reporting that psychedelics, administered to an order arise from the nonconscious, “core” fragmentation of the mind: cognition, conscious emotion, motivation as well as personality susbsystems are self-organized 9 The term means “soul manifesting” in English, as these from and operate with fragmented (unbalanced) ele- compounds cause an altered state of consciousness and mentary particles, as discussed. In the context of inner sensory changes, produce experiences of emotional polarization, negative or positive stimulations (failures communion, oneness, relatedness, and emotional openness (empathogens or entactogens) and are believed to promote or approvals) easily activate negative and positive development of the unused potentials of the human mind affects (anger or idealization) and the corresponding (entheogens). contradictory images of one’s own self and others

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(“bad” or “good”). Such heightened reactivity gives rise Stable instability of the mind: mood/emotions10, to the so called “stable instability” of personality dis- thought, motivation, and behavior. order, which is observable in mental faculties (thought, Mood instability and turbulent emotions motivation, emotion), as well in higher order subsystems, e.g., unstable sense of self, fluctuating identity, Unpredictable swings between opposite moods, fue- turbulent interpersonal relations which oscillate between ling matching shifts in self-image, thought content, devaluetion and idealization frequently of the same motivation, and interpersonal attitudes are typical of person, among others. In fact, the only relatively stable personality disorder. As noted, inner polarization into subsystem of the mind is excessive temperament, which contradictory “either or” affects and images self- and in most cases has contributed to the syndrome in the others makes these individuals prone to oscillate be- first place and continues to perpetuate it. tween periods of optimistic exaltation (reflecting ideali- As discussed, personality disorder arises from the zation of new people and the associated self-image) and homeostatic attempt of the early mind to compensate for disillusionment (reflecting anger and devaluation of the fragmentation and organize through defensive omni- themselves and others, including those previously ideali- potent fantasies. Consequently, the mind is self-orga- zed), owing to failures in maintaining one’s own unrea- nized into an unrealistic and pathological yet a more listic self-image. The unpredictable mood turnarounds stable self-image, basically an impersonation of the are difficult to understand, as they seem to appear from fantasized defensive image (e.g., narcissistic, histrionic, nowhere, driven as they are by idiosyncratic internal antisocial, etc. The process accounts for the duality of agenda rather than by anything appreciably based in the self-subsystem in personality disorder. The domi- reality. One exception to the described mood instability nant compensatory self brings about behavior styles is the stable low-key mood of the schizoid variant. Here, traditionally recognized as clinical variants of persona- emotional detachment serves as a compensatory solu- lity disorder: narcissistic grandiosity, bullying antiso- tion to the core fragmentation (discussed later) thereby ciality, histrionic theatricality, passive-aggressive de- reducing the importance of the interpersonal stage to pendency, paranoid distrust, schizoid detachment, and maintain one’s self-image, which is mostly supported anankastic perfectionism. The dominant self-image unilaterally, in fantasy (interpersonal stage is otherwise coexists with the weaker and split-off real self (the real vitally important in other variants). endangered fragmenteed mind), the latter harboring One should keep in mind that people process sen- fragile self-esteem, exceptional sensitivity to rejection, sory and factual information, including social clues, feelings of inferiority, emptiness and boredom, anger through a highly personal prism, basically a set of uni- and aggression, lack of genuine interest, dysphoria, que expectations reflecting one’s unique personality paranoid fears, among other features. Figuratively, organization. In personality disorder, the patient’s ex- personality disorder can be thought of as “better any pectations are extremized in order to match the unrea- organization, than no organization” where an extre- listic self-image. Such “tunnel-vision” communication mized unrealistic self is the lesser of two evils (the makes these individuals prone to fail own expectations. alternative is disintegration). The two selves co-exist As the most intense emotions are triggered by failures, but are barely aware of each other, divided by “vertical they manifest negative emotions (dysphoria and anger splitting” and mutual disavowal (Kohut 1971). Most in particular) more frequently and more intensely than patients are aware, albeit phenomenally only, of their positive emotions (elation), although the latter can be own fragility and inauthenticity, which stirs up dis- rather impressive as well. turbing disintegration and existential anxieties as well as hypochondriasis. Core dysphoria: the default mood Other subsystems of the mind are also affected: tem- of personality disorder perament traits are poorly contextualized and cognized Dysphoria refers to a variety of chronic and perva- (“untamed”) and frequently lead the mind, character sive but ill-defined negative moods common in all traits subserve the internal need for organization at the variants of personality disorder: emotional distress, expense of social adaptation, identity is diffuse and emptiness and boredom, resentful neediness and depen- changing, and moral values are opportunistic. The dency, sense of mental fragility, inadequacy, irritability, persisting hypofrontality may explain poor capacity of and deeply rooted sense of abandonment, among others. mentalization, underdeveloped theory of mind of others, impulsivity, and lack of empathy, as discussed. Kernberg (2015) describes these individuals as 10 Affect is defined as a nonconscious, short-lived and usually “reflexive” rather than “reflective”. intense psycho-physiologic brain state consisting of subjective Diagnosis of personality disorder must include both conscious experience (emotion, feeling), associated ideas and the shared aspects of fragmentation (the “how” of fantasies, and biologic and behavioral response patterns. The personality or “vertical” diagnosis, as discussed) and the concept of emotion is interchangeable with feeling, both overt signs and symptoms of variant-specific behavior referring to a conscious experience of an affect state. Mood is defined as a pervasive and sustained emotion, spreading over styles (the “what” of personality or “horizontal” diag- the entire mind, including cognition, motivation, and behavior, nosis), as discussed. over a relatively long period of time.

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Such miserly moods in turn fuel negative interpersonal trait13 of HA, most prominent in negativistic-depen- attitudes, notably sarcasm, bitterness, resentment, cyni- dent14, paranoid, narcissistic, and anankastic variants. cism, active and passive aggression, among many Functional trait anxieties are rooted in the fragmented others. The term “core dysphoria” implies its roots in mind: pervasive uneasiness about physical health (hypo- the fragmented personality core or, more precisely, in chondriasis) and psychological safety (disintegration the exhausting and ultimately futile struggle to achieve a anxiety), intense separation anxiety (resulting from unfi- sustained inner stability (Pazzagli & Monti 2000). To nished individuation), anxiety concerned with authen- wit, core dysphoria reflects never ending failures of ticity of existence (existential anxiety), and unique ab- internal expectations. Neuroimaging studies suggest a andonment anxiety, a component of the wider rejection causal association of personality fragmentation, sub- sensitivity syndrome which also includes distrust in optimal prefrontal network development and organi- one’s own ability, lack of self and object constancy, zation, and chronic low mood in personality disorder, among other phenomena. Separation and abandonment justifying the term “core dysphoria”: a dysfunctional anxiety are usually intertwined and common with all frontal lobe was found to be associated with intra- variants of personality disorder, excepting the schizoid psychic and interpersonal features indicative of pro- variant. Individuals with personality disorder are “stuck” found personality pathology in young adult females in the separation-individuation phase, having not achie- with chronic dysphoria (Lyoo et al. 2002). ved a full separation and even less so individuation, they show a peculiar intolerance of being alone. Recurrent episodes of atypical depression Continual struggle to compensate for inner fragmentation stirs anxieties unique to personality disorder The constructs of atypical depression and “border- (referred to as “fragmentation anxieties”), regardless of line” (fragmented) personality overlap. In most cases, the variant and even in the context of low biological fragmented personality can be found are the root of anxiety, e.g., in maladapted individuals with heritably atypical depression. An episode of atypical depression low or moderate HA. Fragmentation-related trait anxie- typically occurs after major failures, relationship break- ties arise as a function of (i) continual danger of disinte- ups, disappointments, in short, it follows unmet expec- gration, which fuels doubts about own psychological tations in the external environment. Atypical depression safety (disintegration anxiety), or (ii) precarious cohe- is more severe than core dysphoria, but the two may co- sion of the compensatory self, which fuels doubts about exist (a variant of “dual depression”). Clinically, episodes one’s own authenticity and purpose (existential an- of atypical depression are distinguished from typical xiety). Both anxieties are likely unique to humans who, depression based on (i) preserved reactivity to pleasurable in developing self- awareness, opened the door to self- stimuli (the patient responds to “good news”), reversed doubt, thereby expanding the repertoire of fear-inducing vegetative symptoms of (ii) increased appetite or weight stimuli to abstract threats and metaphysical questions of gain and (iii) hypersomnia, (iv) heavy or leaden feelings purpose and meaning. in limbs, and, as the cardinal feature, (v) profound and chronic rejection sensitivity11 not limited to mood distur- The natural course of fragmentation anxieties is fluc- bance. Rejection or abandonment sensitivity refers to a tuating, reflecting the fluctuating degree of compen- chronic, intense, irrational and usually unjustified expec- sation achieved by deviant functioning. Because of such tation of rejection and rapid overreaction to it. The waxing and waning course, fragmentation anxieties may phenomenon is believed to be rooted in the continuing be misdiagnosed as state anxiety, frequently misleading need for selfobjects: the patient dreads being rejected by treatment away from the root cause of the problem. his or her selfobject as this threatens not only the integrity Fragmentation anxiety requires long- term reconstruc- but also the survival of his or her own self (selfobjects tive psychotherapy with only sporadic and short- term define and maintain the patient’s sense of self). The use of anxiolytics during periods of exacerbations. Such dynamics is indicative of an early developmental deficit “comfort pharmacotherapy” is indicated because surges and is highly suggestive of personality disorder. of fragmentation anxiety can lead to the formation of new symptoms, deepening of existing symptoms, or to A rich assortment of trait anxieties12 regression. characterize personality disorder Disintegration anxiety can be thought of as a psychological equivalent of the fear of dying. It includes Biological trait anxiety refers to stable anxieties a profound feeling of mental fragility experienced by associated with the heritably excessive temperament the patient who is struggling to maintain a cohesive

11 Rejection sensitivity and abandonment anxiety are for all 13 High HA or anxious temperament is clinically presented and practical purposes equivalent concepts diagnosed as generalized anxiety disorder (GAD). 12 “Trait” anxiety refers to stable individual dispositions to- 14 We combine the DSM passive aggressive and dependent wards anxiety (“how the person typically is” - a longitudinal subtypes into the negativistic- dependent variant of personality view) while “state” to anxietyrefers to episodic anxieties disorder, based on our clinical observations that submissi- which arises from changes in internal and external conditions veness and passive aggression regularly co- occur in this (“how the person currently is” - a cross- sectional view). particular variant.

7 Dragan Svrakic, Mirjana Divac-Jovanovic & Naazia Azhar: AN INTEGRATIVE MODEL AND DYNAMIC NOSOLOGY OF PERSONALITY DISORDER: PART 2: SYMPTOM-BASED PHARMACOTHERAPY Psychiatria Danubina, 2019; Vol. 31, No. 1, pp 2-17 sense of self and thus feels psychologically unsafe. and daydreaming, with full control over mental events, Kohut (1977) understood this type of anxiety as the which is instrumental in organizing internal fragments patient’s “dawning awareness” that the cohesion of his (a form of unilateral adaptation). or her self is precarious and could easily disintegrate The main trait vulnerability for the schizoid variant under adverse psychological circumstances. Similarly, is low social RD (social disinterest and detachment), Klein (1952) talks about the “fear of invasive malevo- coupled with low NS (stoicism, low impulsivity), low lence” within paranoid-schizoid position15, which (the HA (low anxiety, low fear of uncertainty), and low PE fear) is experienced as coming from the outside but (indolence, lack of ambition). It is this composite of ultimately deriving from the projection of the person’s globally hypoactive temperament, coupled with perso- imminent annihilation fears causing such paranoia. A nality fragmentation, and compensatory withdrawal form of disintegration anxiety is hypochondriasis, aka into fantasy that we consider a bona fide schizoid “health worry anxiety”. The person demands diagnostic personality disorder.16 workups and does not respond to reassuring findings. Hypochondriasis arises from the core problem of frag- Cognitive distortions, dissociative phenomena, mentation generating a deeply rooted distrust in one’s and psychotic symptoms own health, here physical health. It is thus usually suggestive of personality disorder, particularly narcis- Chronic and subpsychotic (“soft”) cognitive distor- sistic, histrionic, antisocial, and paranoid. tions observed in personality disorder fall into two Existential anxiety refers to one’s dim but unmistak- broad categories: able awareness of own pretense (“as if”) and is rooted in Symptoms of loose (undisciplined) cognitive func- fragmented personality. This form of trait anxiety arises tioning reflects a strong presence of the primary pro- from the ultimate inability of individuals with perso- cess, dominated by wishes, conflicts, affects, and fan- nality disorder to develop an authentic sense of meaning tasy (Auchincloss & Samberg 2012). The phrase “strong and true calling, but rather live by the dictate of false presence” is used to draw contrast with omnipresent motivations and assumptions inherent in the compen- primary process in psychosis. The concept of primary satory self-image. Such artificial existence feels like a process refers to nonlinear, often nonverbal thinking fabrication without genuine authenticity, passion, and which employs concrete symbolization, condensation, purpose. Most patients distantly recognize their “as if” and displacement, resulting in disregard for logical personality which is suggestive of some, albeit only connections or contradictions (e.g., a fallacious attribu- phenomenal, passive noticing of their own pretense tion of causal relationships between actions and events). (discussed earlier). Individuals with personality disorder characterristically manifest limitations in reality testing both in terms of deficits in the subtle aspects of interpersonal functioning Withdrawal from the social world (Kernberg 2015), and in their sense of self, filled with as unilateral adaptation: emotional detachment fantasies only vaguely recognized as wishful. The ap- and social disinterest proximately even mixture of primary and secondary Reserved and aloof emotions and social disinterest process distinguishes personality disorder from neuro- are occasional with paranoid, anankastic, and antisocial- ses, where the secondary process, based on logic, schizoid individuals, and are typical of the schizoid reality, and problem-solving, is dominant. variant of personality disorder. The defining features of Symptoms of biased cognitive functioning arise the latter are social disinterest (referring to a peculiar from the unrealistic self-image which dictates variant- lack of desire for social contacts or sexual experiences), specific cognitive distortions and motivational priorities. preference for a solitary lifestyle and activities (“loners”), These are made possible by the presence of the primary indifference to praise or criticism, blunted emotions process. Biased cognition therefore can be thought of as a (negative and positive alike), excessive daydreaming special case of loose cognition characterizing a particular (autistic fantasy), and excessive introspection (rumina- variant of personality disorder. For illustration, egocentric tive self-examination). In contrast to other variants, perception of reality, whereby events are primarily defi- schizoid individuals rarely seek interpersonal conflicts, ned through the prism of one’s own wishful needs, is a do not actively disturb the environment, stay isolated pervasive cognitive distortion present in all variants but and keep to themselves, and rarely break laws or engage with a differing theme: misattribution of admiration by in risky behaviors. In contrast to other variants which others of narcissistic personalities (“I am admired, vitally need the interpersonal stage to maintain own therefore I am”), pervasive suspiciousness of paranoid self-image, individuals with the schizoid variant need personality (“I am persecuted, therefore I am”), sexua- minimal interpersonal approval. They appear as if they lization of interpersonal contacts of histrionic personality have abandoned bilateral interactions with the society (“I seduce, therefore I am”), alpha-type dominance of and have withdrawn into the autistic world of fantasy

16 In contrast to schizoid features without personality disorder 15 Paranoid-schizoid position is equivalent to fragmented manifested by individuals within the “Schizophrenia personality spectrum”.

8 Dragan Svrakic, Mirjana Divac-Jovanovic & Naazia Azhar: AN INTEGRATIVE MODEL AND DYNAMIC NOSOLOGY OF PERSONALITY DISORDER: PART 2: SYMPTOM-BASED PHARMACOTHERAPY Psychiatria Danubina, 2019; Vol. 31, No. 1, pp 2-17 antisocial personality (“I intimidate, therefore I am”), stable personal goals are not the best set of features for or withdrawal from external reality and reliance on successful predation. The latter requires effective im- uncontested fantasy of schizoid personality (“I define pulse control and executive function, both a function of who I am”), among others. cognitive networks, with less involvement of the hypothalamus and limbic structures. The predator exhibits Individuals with any variant of personality disorder patience and careful planning to disguise his or her can more or less transiently regress to the psychotic intentions, choose a vulnerable target, and strategize level of mental functioning, especially those with a the attack, which is typically not a response to an family history of psychosis (i.e., those genetically closer immediate threat or provocation but is driven by the to the threshold for psychosis) and/or when under stress expectation of gain. (hence the label “brief reactive” psychoses). The inten- sity of stress-related anger or paranoid fears may erode the precarious stability of the mind achieved through the Character disorder: a useful but compensatory deviant self. One may speculate that in- abandoned concept tense negative affects in the context of severe stress can The concept of “character disorder” captures the break through the protective barrier erected by the pathology of social behavior, including career predation, splitting mechanism and thereby open the floodgates for which is not associated with the described neural and the primary process to temporarily impair reality testing, mental pathology of personality disorder. Rather, career with psychosis as a manifestation. These episodes are predation reflects one’s adaptive strategy by choice, indeed of short duration, from several hours to several whether intuitive or deliberate, usually made in adoles- days, and are thus amenable to confrontation and, later cence or early adulthood. To refine public, forensic, and in therapy, to interpretation. scientific understanding of antisociality and criminality, we advocate that the concept of “character disorder” be Anger and aggression: the default affect - reinstated as a diagnosis19. The concept captures not behavior complex of personality disorder only career predators, as discussed, but also a spectrum of other egotistic, repulsive, illegal, and/or obnoxious Kernberg (2015) provides an insightful analysis of social behaviors (arrogance, theft, entitlement, greed) in ubiquitous anger and aggression in personality disorder: the context of statistically integrated personality but massive negative representations make the individual corruptible character and morality by choice, i.e., predisposed toward experiencing others as persecutory intuitive or deliberate strategy to obtain resources and/or and/ or rejecting. The experience is easily activated by get ahead at the expense of others. negative stimulation in interactions, which puts the patient in a chronically assumed role of a victim. Such a fixed persecutor-victim relationship leads to anger and Interpersonal relations: conflict as the only aggression which the patient, by the mechanism of resource to maintain the sense of self projective identification, attributes to others. In order to Personality disorder is experienced intrapersonally, maintain the omnipotent power position and sense of expressed interpersonally, and diagnosed in both con- control, the patient (victim) seeks conflicts with others texts. Accordingly, DSM-5 and ICD-11 place diagnostic (persecutors), and eventually he or she (the patient) emphasis on both self-pathology and interpersonal becomes the victimizer. This dynamics makes individuals relations. As noted, an adaptively suboptimal mind, as is with fragmented personality prone to aggression, usually the case with personality disorder, continues to need 17 impulsive-affective interpersonal conflicts in the con- sources of organization, both internally (through fan- text of (mis)perceived threats to one’s compensatory but tasy) and interpersonally (through a continual need for precarious self-image. This pattern explains the presence selfobjects who define and maintain the sense of self). of aggression in all clinical variants of personality Interpersonal conflicts are actively sought to change 18 disorder, fearful , impulsive, and aloof alike. The act of others’ reactions to one’s own maladaptive style or to impulsive aggression is not gain oriented but is an end coerce them into following the expected exposition sup- unto itself, aimed to destroy or correct the perceived plied by the supporting cast of selfobjects (alloplastic provocation. Violence is generally rare excepting the adaptation). The ”provocateur” is important for the antisocial variant, but even here not invariable psychological stability of the provoked, who thus cannot Predatory aggression is rare with personality dis- just avoid confrontation, but instead feels compelled to order. Poor executive function, erratic moods, and un- re-establish the image through the conflict. Such hostile interpersonal conflicts further cement the polarization of the inner world and thereby perpetuate the core 17 Here, aggression does not denote a heritably high biological disposition, but rather arises from the described dynamics of psychopathology of all variants, excepting the schizoid personality disorder. Aggression as a heritable disposition, variant where such conflicts are rare. related to low frustration tolerance and impulsivity associated with excessive NS, acts as early trait vulnerability for antisocial and histrionic variants of personality disorder. 19 The term and concept have been abandoned by the DSM 18 Passive-aggression in the negativistic-dependent variant. and ICD systems.

9 Dragan Svrakic, Mirjana Divac-Jovanovic & Naazia Azhar: AN INTEGRATIVE MODEL AND DYNAMIC NOSOLOGY OF PERSONALITY DISORDER: PART 2: SYMPTOM-BASED PHARMACOTHERAPY Psychiatria Danubina, 2019; Vol. 31, No. 1, pp 2-17

Interpersonal stage is where the deviant compen- overall severity of the disorder. However, we agree with satory self finds its materialization (fantasy is another Blais et al. (2016) that “modest empirical evidence and option, but rarely sufficient, excepting the schizoid considerable clinical benefits” continue to support the variant). The dependence on interpersonal relations to use of medications in the overall treatment of perso- maintain the deviant self-image may explain why trait- nality disorder. Symptom-based pharmacological sup- aggression sometimes alternates with helpless depen- pression of affects and impulses helps clear the way for dency: the dynamics reflects a frustrating stalemate corrective emotional experience in psychotherapy and between the vital need for inner organization and one’s also helps suppress disruptive affects in real life, an inability to achieve it without the supporting roles of important early clinical goal. selfobjects i.e., others. Each variant of personality disorder demonstrates its own specific style of social The symptomatic architecture of personality deviance, the patient’s common style of interaction as disorder: four main symptom domains the means to maintain inner organization. These variant- specific styles define interpersonal contacts. Individuals In symptom-based approach, symptoms are targeted with the schizoid, paranoid, and antisocial variant of outside of their neural and mental mechanisms: dys- personality disorder are characterized by social coldness phoria with antidepressants, unstable mood with mood and disinterest, lack of empathy, low intimacy, and stabilizers, and so on. The rationale for drug choice is occasional predatory crime (antisocial and paranoid based on analogy with treatments proven effective for variants are more vindictive and domineering than the “major” syndromes (depression, mania, anxiety and schizoid variant). With exhibitionistic and intrusive psychosis), rather than a theory driven approach spe- variants (antisocial, narcissistic, histrionic), the distin- cific for personality disorder. This lack of specific guishing features are grandiosity and social coldness hypothesis about underlying mechanisms to guide (narcissistic and antisocial), or sexualization of all treatment is the fundamental difference between mecha- relationships, theatricality, and rush into intimacy (his- nism-based and symptom-based pharmacotherapy of trionic). Reticence, rigidity, and perfectionism charac- personality disorder. Both approaches are bottom-up, terize interpersonal relationships of the anankastic as both focus on heightened subcortical affect reac- variant, while passive-aggression combined with de- tivity, but they differ in another important way: pendency characterize the negativistic-dependent va- symptom-based approach suppresses the pathological riant. As noted, the shared affect state for all variants equilibrium in which affects dominate cognition, while is resentful anger of a victim manifested as fantasies of mechanism-based approach aims to activate homeo- omnipotent control of others and frequently as overt static equilibration of a specific trait vulnerability, aggression (one exception are the idealized selfobjects, which now can be integrated into the mind in a natural although this can quickly change). Each variant shows way (Svrakic et al. in prep.). However, symptom-based a significant association with vindictiveness, social approach may be closer to the root psychobiology of distrust and suspiciousness, and a decreased concern personality disorder than one may think. The four about the needs of others. All of these features are empirically derived symptom domains (see below) not accompanied by minimal personal distress, suggestive of only correspond to the latent genotypic-phenotypic ego-syntonicism. All variants are also characterized by architecture of personality disorder (Livesley et al. 1998) opportunistic, corruptible, and non-abstracted morality in but also to the high (extreme) ends of normal tempera- interpersonal relationships, usually resulting in minor ment traits (Cloninger et al. 1993), the latter are esta- transgressions and manipulation, only exceptionally in blished as trait vulnerabilities for personality disorder major violent crimes or predation, as discussed. Finally, (Svrakic et al. 1993). The high correspondence between all variants manifest character traits of social intolerance, observable symptoms arranged into domains, latent egocentricity, selfishness, greed, etc., because character phenotypic-genotypic dimensions, and normal albeit development was primarily guided by the mandate for excessive temperament traits narrows, but does not close internal organization, not to maximize social adaptation, the gap between symptom-based and mechanism-based as is normally the case. approaches, as indicated by the non-selectivity of symptomatic pharmacotherapy which affects multiple SYMPTOM DOMAIN symptom domains simultaneously (discussed below). BASED TREATMENT OF The symptom-domain pharmacotherapy targets phe- PERSONALITY DISORDER nomenology and symptoms that are not readily recog- nizable to be typical of individual variants of personality For the majority of the described symptoms of per- disorder, e.g., in DSM-5 criteria (APA 2013). This is sonality disorder the most effective treatment is recon- because the symptom-based approach is more effective structive in-depth psychotherapy which targets the core in suppressing symptoms of shared fragmentation (such problem through corrective emotional experience. Lieb as mood instability, core dysphoria, trait anxiety, anger et al. (2010) review drug trials of “borderline” perso- and aggression, etc.) than those of variant specific beha- nality and conclude that medications may be effective in vior styles (narcissistic, histrionic, dependent, etc). Sim- treating turbulent affects and behaviors but not the ply put, no available medication is capable of treating

10 Dragan Svrakic, Mirjana Divac-Jovanovic & Naazia Azhar: AN INTEGRATIVE MODEL AND DYNAMIC NOSOLOGY OF PERSONALITY DISORDER: PART 2: SYMPTOM-BASED PHARMACOTHERAPY Psychiatria Danubina, 2019; Vol. 31, No. 1, pp 2-17 narcissistic or histrionic attitudes, as these are compen- The four empirically derived symptom domains are: satory epiphenomena, emerging mental properties which Mood and anxiety dysregulation (chronically unst- organize the fragmented mind. These variant-specific able mood, core dysphoria, recurrent atypical de- symptoms are not suitable as targets for pharmaco- pression, chronified anxieties); therapy. The latter is most effectively organized around Behavior dysregulation (interpersonal affective ag- four empirically derived domains of symptoms, each gression, poor impulse control); rooted in personality fragmentation and thus each shared by all variants to a variable degree, although Emotional detachment (social disinterest, low intimacy, with some predilection for certain variants (e.g., lack of empathy, restricted expression of emotion); impulsivity is most impressive in histrionic, antisocial, Cognitive dysregulation (loose and biased cognition, and narcissistic variants). transient psychoses).

Table 1. Pharmacotherapy of four target symptom domains of personality disorder Target Symptom Domain Drug of Choice Comments I MOOD DYSREGULATION (UNSTABLE MOOD, DYSPHORIA, DEPRESSION, TRAIT ANXIETY) Mood instability/lability LITHIUM, VALPROATE, Tx of choice: RECONSTRUCTIVE LAMOTRIGINE PSYCHOTHERAPY Low dose SGPs (aripiprazole, (cognitive stabilization of mood) quetiapine) (chemical suppression of mood instability) Core dysphoria (default mood) No effective pharmacotherapy Tx of choice: RECONSTRUCTIVE PSYCHOTHERAPY Atypical depression (frequent) MAOIs (phenelzine) TCAs ineffective for atypical depression SGPs (aripiprazole, low dose clozapine) Biological anxiety (excessive HA) SSRIs, GABA ENHANCERS No benzodiazepines (abuse risk) (esp. pregabalin), NMDA antagonists (ketamine) Azapirones (buspirone) Fragmentation “core” anxiety “comfort pharmacotherapy”: Tx of choice: RECONSTRUCTIVE disintegration, existential SGPs, pregabalin PSYCHOTHERAPY hypochondriasis (aggressive pharmacotherapy (numbing) TCAs, SNRIs (milnacipran, duloxetine) may mask important cues in psychotherapy) II BEHAVIOR DYSCONTROL (IMPULSIVITY, AGGRESSION, VIOLENCE) Impulsive-Affective aggression SSRIs, 5-HT1A/B agonists (buspirone) No benzodiazepines (disinhibition) (default affect state) SGPs (aripiprazole, risperidone) GABA ENHANCERS (pregabalin, Positive allosteric modulators of GABA gabapentin) A receptors unpredictable BETA BLOCKERS (propranolol) (benzodiazepines, barbiturates) MAOIs Opioids (buprenorphine) Lithium III SOCIAL DISINTEREST, LOW INTIMACY. RESTRICTED EMOTIONAL EXPRESSION Social amotivation Buprenorphine Pharmacotherapy largely ineffective (“asociality”) SGPs (aripiprazole) Tx of choice: PSYCHOTHERAPY (metacognitive, mentalization) followed by RECONSTRUCTIVE PSYCHOTHERAPY IV COGNITIVE PERCEPTUAL DISTORTIONS and PSYCHOTIC SYMPTOMS Brief reactive psychotic episodes SGPs (risperidone) STRESS MANAGEMENT STRESS SUPRESSION (chemical - (better coping) mood stabilizers, SGPs, antidepressants, (exercise, meditation) anxiolytics) Sub-psychotic chronic cognitive SGPs (uncertain effectiveness) Tx of choice: RECONSTRUCTIVE distortions (default thinking) (risperidone, aripiprazole) PSYCHOTHERAPY (“loose” and/or biased cognition) Legend: CAPITAL LETTERS - FIRST LINE and MAJOR INDICATION; lower case letters - second line; SGPs - second generation psychotropics; BNZD - benzodiazepines; SSRI - selective serotonin reuptake inhibitors; SNRI - serotonin norepinephrine reuptake inhibitors; GABA - gamma aminobutyric acid; MAOI - monoamine oxidase inhibitors

11 Dragan Svrakic, Mirjana Divac-Jovanovic & Naazia Azhar: AN INTEGRATIVE MODEL AND DYNAMIC NOSOLOGY OF PERSONALITY DISORDER: PART 2: SYMPTOM-BASED PHARMACOTHERAPY Psychiatria Danubina, 2019; Vol. 31, No. 1, pp 2-17

Pharmacotherapy of symptom domains: to benefit unstable moods via serotonergic and dopami- non-selective but clinically useful nergic effects, as both of these brain systems are relevant in mood and anxiety symptoms. Reconstructive in-depth Pharmacotherapy targeting the above four domains psychotherapy is more specific for the mood instability of is non-selective, as medications affect multiple domains personality disorder and is thus the treatment of choice simultaneously. For example, second generation psy- (“mental stabilization”). chotropics (SGPs)20 are used for all four symptom domains (e.g., mood and anxiety dysregulation, behavior dysregulation (aggression), emotional disinterest, and Symptomatic management of low moods cognitive symptoms of psychosis). Similarly, seroto- of personality disorder nergic antidepressants are the treatment of choice for Core dysphoria is the default mood of fragmented mood, anxiety, and aggression domains. Such non- personality, and is notoriously refractory to pharmaco- selectivity may reflect a number of factors, the most therapy. Some options are presented in Table 1. Cor- likely being that the four domains are heterogeneous rective emotional experience (“re-parenting”) in expert entities, co-regulated by anatomically overlapping, neuro- psychotherapy helps both the dysphoric mood and the nally intertwined, and functionally interrelated brain co-occurring features indicative of fragmentation, such networks involved in mood, motivation, and cognition. as rejection sensitivity or clinging dependency (Beatson Recommendations for pharmacotherapy targeting symp- & Rao 2012). tom domains are summarized in Table 1. Any form of episodic depression comorbid with per- The recommendations listed in Table 1 are made sonality disorder, whether typical or atypical, is more based on the available, albeit rather limited literature as resistant to traditional antidepressants and electrocon- well as on the authors’ clinical experience. The evi- vulsive therapy (ECT), than depression in individuals dence for the recommendations is generally weak, this with no personality disorder. Atypical depression is be- reflecting lack of good clinical studies rather than lieved to be biologically distinct from major depression negative findings. Table 1 is self-explanatory. Thus, we because of its inferior response to standard antidepres- have chosen to address a few selected topics that might sants and ECT, and superior response to phenelzine, a be of interest to the reader. MAOI. For phenelzine nonresponders, instead of switching to a non-MAOI antidepressant, augmentation with Symptom domain I: Mood Dysregulation or switching to one of the SGPs may be more effective, and Anxiety Syndromes although this has not been studied systematically. This symptom domain includes mood instability, Given its frequent comorbidity with major depres- core dysphoria, recurrent atypical depressions, episodes sion, some have proposed that borderline (fregmented) of major depression, and a spectrum of trait anxieties. personality merely represents an unusual manifestation Based on Livesley et al. (1998), we include trait anxiety of unipolar depression. As noted earlier, the most com- in the mood dysregulation domain. pelling evidence against such spectrum relationship is Although non-bipolar in nature, mood instability of that treatment of major depression does not improve fragmented personality is treated by traditional mood core borderline symptoms, while psychotherapy of bor- stabilizers, lithium, valproate, and lamotrigine in parti- derline personality tends improve both personality and cular (the latter slightly preferred by most experts). As depression (reviewed in Beatson & Rao 2012). second-line, low to moderate doses of atypical SGPs stabilize mood by unknown but likely diverse mechanisms. All have been approved by Food and Drug Administra- Prozac “poop out”: is it time to use pulse tion (FDA) for bipolar disorder and all show modest treatments for the phasic illness of depression? effectiveness in suppressing mood instability fueled by The recent increase in treatment refractory depres- the specific dynamisms of personality disorder as well sion, now estimated at about 30% of all cases, coincides (“chemical suppression”). One explanation for such un- with the expanding use of selective serotonin reuptake expected but welocme effectiveness is that all moods, inhibitors - SSRIs, usually after a good initial response whether biological, internally generated, or reactive by (the phenomenon has been dubbed “Prozac poop-out” nature, ultimately materialize within their respective or “tachyphylaxis”). Dual reuptake inhibitors (tryciclic neurobiological circuits and become conscious by the antidepressans - TCAs and serotonin-norepinephrine work of the same general network of cognition. Here, reuptake inhibitors - SNRIs) appear to have lower rates pharmacotherapy affects both cortical and subcortical of progressive decrease in response (Posternak & circuitry in a global pattern, by general slowing of neu- Zimmerman 2005). Tachyphylaxis is hypothesized to ronal activity (lithium, valproate), enhancing inhibitory reflect pharmacodynamic tolerance (desensitized recep- GABA activity (valproate), or suppressing activating tors), pharmacokinetic tolerance (decreased quantity of glutamatergic mechanisms (lamotrigine). SGPs are likely medication reaching the target site), or new onset apathy, all documented with SSRIs. 20 The term “psychotropics” is preferred over “antipsychotics” The increase in treatment resistance possibly related for these medications, as they are commonly used in non- to SSRIs has led many to question the typically long psychotic syndromes, such as anxiety and affective disorders.

12 Dragan Svrakic, Mirjana Divac-Jovanovic & Naazia Azhar: AN INTEGRATIVE MODEL AND DYNAMIC NOSOLOGY OF PERSONALITY DISORDER: PART 2: SYMPTOM-BASED PHARMACOTHERAPY Psychiatria Danubina, 2019; Vol. 31, No. 1, pp 2-17 treatment duration, frequently lasting years and even Symptom domain II: Dysregulation of Behavior decades. Criteria for discontinuation of antidepressants (Aggression, Impulsivity, Violence) are vague. Clinicians are reluctant to discontinue anti- Anger and aggression are default affect-behavior traits depressants to avoid relapse, a real risk for many patients. in personality disorder and perpetuate its psychopatho- However, a significant number of patients taking anti- logy. As discussed, chronic interpersonal aggression occurs depressants relapse anyway (cca. 20-44% of patients on as a reaction to misperceived threats to one’s own compen- SSRIs, lower for TCAs), so the relapse rates cannot be satory but precarious self-image. Here, we limit our dis- much worse with discontinuation. A few logical stra- cussion to impulsive affective aggression, by far the most tegies to reduce the incidence of refractory depression frequent form of aggression in personality disorder. The are listed below. We emphasize that none has been neural mechanisms of affective aggression are reviewed supported by systematic research. One possibility is to to lay the groundwork for pharmacological considerations. treat depression as a phasic illness in a phasic manner (aka “pulse treatment”) with SSRIs. Drawing from our The neuroanatomy of human aggression concept of harnessing homeostasis for healing21, drug holidays during remissions may help preserve the Two networks, one primarily subcortical (aggression brain’s ability to activate its homeostatic response in case as instinct), the other primarily cortical (aggression as SSRIs are needed again. Mood stabilizers (lamotrigine decision), both intersecting in the amygdala, are pos- in particular) may reduce the risk of relapse during the tulated to underlie the complex phenomenon of human SSRI holidays. Another strategy is to alternate between aggression (Victoroff 2017). The cortical network (invol- SSRIs, NRIs, and SGPs at regular intervals, which ving the ventromedial, orbitofrontal, dorsolateral PFCx, would mean even switching patients who are doing well the anterior cingulate cortex, with the key nexus in the on a certain drug. amygdala) regulates aggression as a behavior assessed to be the only resource in the given context (e.g., protecting one's child against criminal abduction in progress). This Comfort pharmacotherapy for trait anxieties is a partly conscious process capable of either suppres- As discussed, a rich variety of trait anxieties is ob- sing automatic amygdala reactions or to proceed with served with personality disorder, from biologically an- aggression if deemed necessary. The subcortical network xious temperaments (heritably high HA), to a spectrum regulates nonconscious, instinctive aggression in emer- of anxieties rooted in the fragmented personality core, gencies, e.g., a reflex reaction towards the home intruder such as disintegration anxiety and hypochondriasis, who threatens the homeowner’s life. The subcortical cir- existential anxiety, and abandonment anxiety. Heritably cuits of aggression involve the hypothalamus, the nucleus high HA is effectively treated with SSRIs, GABA- accumbens/septal region, the dopaminergic ventral teg- enhancers – especially pregabalin22, mild NMDA anta- mentum, the serotonergic raphe nuclei, and the dorsal gonists (ketamine), and buspirone (a partial 5-HT1A periaqueductal grey (PAG), again with the key nexus in receptor agonist). Treatment of choice for fragmentation- the amygdala (Victoroff 2017). The same subcortical cir- related trait anxieties is reconstructive in-depth psycho- cuitry also regulates a number of other instinctive social therapy. Pharmacological numbing of these trait anxieties behaviors (mating, dominance, etc.) and is known as “sub- does not address the root cause, and in fact could mask cortical social behavior network” in animals (Newman important cues in psychotherapy. Medication is thus not 1999). In personality disorder, both of these loops contri- used beyond the minimum amount and time necessary to bute to trait aggression. First, the hypofunctional PFCx ensure some comfort (“comfort pharmacotherapy”). Anti- renders subeffective cortical feedback regulation of af- depressants are not very effective for hypochondriasis, fect-driven behaviors. Second, most variants of perso- but TCAs may be more effective than SSRIs, although nality disorder have a heritably heightened fear and anger reactivity, both of which predispose them to aggression the latter have not been studied as frequently. via subcortical activation. The neuroanatomy and neurophysiology of aggression are complex (which is under- standable given its evolutionary significance), making pharmacotherapy of aggression equally complex.

21 Pharmacotherapy can be designed to activate corrective The neurophysiology of impulsive aggression: restoration of homeostasis to optimize all relevant participants in a complex trait. The class of SSRIs provide example of serotonin (5-HT) deficiency at the root 23 such on demand homeostatic recalibration: the initial increase of escalated aggression in extracellular serotonin, a mechanistically fundamental mole- We summarize the vast literature on the neurophy- cule in anxious temperaments, triggers weeks of homeostatic siology of escalated affective aggression as follows: phasic neuroadaptations which eventually downregulate the central serotonergic system. This is widely believed to be responsible spikes of 5-HT release form the dorsal raphe nuclei to the for the SSRIs efficacy in depression and anxiety states, now both believed to be “hyper-serotonergic”. 22 Pregabalin has been approved in Europe for GAD, a clinical 23 Serotonin deficiency does not play a role in adaptive aggres- name for heritably high HA without personality disorder. sion (i.e., aggression within the norms for a species).

13 Dragan Svrakic, Mirjana Divac-Jovanovic & Naazia Azhar: AN INTEGRATIVE MODEL AND DYNAMIC NOSOLOGY OF PERSONALITY DISORDER: PART 2: SYMPTOM-BASED PHARMACOTHERAPY Psychiatria Danubina, 2019; Vol. 31, No. 1, pp 2-17 medial PFCx are believed to contribute to the initiation Polymorphisms of the monoamine oxidase A (MAO and maintenance of aggressive outbursts in social con- A) gene appear to facilitate affective aggression by mo- flicts (Takahashi et al. 2015). Such bursts in 5-HT acti- dulating the structure and function of synaptic glutama- vity in individuals prone to escalated aggression lead to tergic NMDA receptors in the PFCx, ultimately affec- low basal 5-HT neurotransmission, a neuroadaptive down- ting cortical control of aggression. Clinically, MAO regulation in habitual aggressors (this is the basis for the inhibitors can be useful in affective aggression triggered well-known “serotonin deficiency” hypothesis of aggres- by provocation, although the result may in part may be a sion). The 5-HT deficiency in turn compromises seroto- function of improved atypical depression. nergic regulation of the cortical glutamatergic neurons Finally, as mentioned, opiates have a serenic effect. and their feedback to the limbic system and midbrain/ Suppression of defensive rage is believed to be me- brainstem nuclei, notably the dorsal raphe nuclei, the diated via µ-opioid receptors in the PAG. This mecha- ventral tegmentum, and the locus-coeruleus, affecting in nism opens the door, at least theoretically, for partial µ- the process the serotonergic, dopaminergic, and nor- receptor agonists, like buprenorphine, to be tried in adrenergic modulation of aggression. This results in, human affective aggression. respectively: i) more phasic bursts in 5-HT release to the Multiple double-blind trials have shown the efficacy medial PFCx, ii) dopaminergic potentiation, permission, of lithium salts in the treatment of affective aggression and reinforcing of victorious aggressive encounters, and at therapeutic levels for mania. Similar efficacy has iii) noradrenergic potentiation of aggression at the level been reported for combinations of lithium either with of hypothalamus and PAG. As a general rule, glutamate SGPs or with many anticonvulsants (reviewed in Comai may function to exaggerate the excitability of the neural et al. 2012b). The exact nature of lithium’s anti-aggres- players involved in aggressive behavior, particularly sion effectiveness has not been clarified. It is likely multi- when aggression is intense, i.e., glutamate may sensitize faceted (reviewed in Beaulieu & Caron 2008, Pasquali et an individual to become more aggressive (Miczek & Fish al. 2010). Lithium’s cellular effects on second messanger 2005). GABA, by contrast, generally inhibits aggression, pathways that modulate neuronal excitability, a possible as do opioids and serotonin. antimanic mechanism, may also stabilize affective aggressive outbursts and, as discussed, mood instability. Pharmacotherapy of affective aggression There is some evidence that, in a chronic treatment para- With the above in mind, SSRIs and GABA-enhan- digm, lithium upregulates glutamate reuptake and de- cers24 are first line treatment of affective aggression. In creases glutamate release, another possible antimanic addition to SSRIs, a number of other drugs suppress the mechanism (reviewed in Hahn et al. 2004) which may phasic spikes in 5-HT release (necessary for the initia- also help the individual to control escalated aggression. tion of aggression as noted), most notably the SGPs which have both 5-HT2A antagonism and 5-HT1A Symptom domain III: Social Disinterest, Low partial agonism (aripiprazole, risperidone) and 5-HT1A Intimacy, Restricted Emotional Expression and 5-HT1B autoreceptors agonists (buspirone in parti- Emotional detachment, reserved and aloof emotions, cular). The brain’s noradrenergic system may have a emotional poverty, and disinterest in social relations are permissive role in aggressive behavior, facilitating fight most frequently observed with schizoid, paranoid, anan- over flight in response to a challenge, perhaps at the kastic, and antisocial individuals the latter with prominent level of the hypothalamus (reviewed in Siegel & Victo- schizoid traits. To our knowledge, no data exist for roff 2009). Hence, noradrenergic blockers (“beta-blo- pharmacotherapy of the globally hypoactive tempera- ckers”) may suppress such potentiation of aggression. ment of schizoid personalities. Clozapine has been The dysregulated accumbal and cortical dopamine, shown to alleviate negative symptoms in with Schizo- reflecting the PFCx overactivation of the ventral teg- phrenia, where social withdrawal reflects “primary mentum, the source of dopamine for the meso- limbic- asociality” with specific neural correlates (Kaiser et al. cortical pathway, may play a role in the incentive 2016). It is not clear whether clozapine, or any other salience but not in the significant modulation of offen- drug, may affect the secondary asociality of schizoid sive aggression (Miczek & Fish 2005). The activated personality, here a compensatory maladaptive style. ventral tegmentum also projects to the medial hypo- Aripiprazole, a ligand-biased partial D2 and D3 ago- thalamus and other limbic structures, which may facili- nist (“smart drug”) with documented benefits for schi- tate both offensive and defensive rage. Not much evi- zotypal symptoms but, to our knowledge, no studies in dence exists for the efficacy of dopaminergic receptor schizoid personality disorder may be tried (here me- blockers in suppressing the incentive salience of and/or chanism-based and symptom-based approach overlap)25. in revoking permission for aggression.

25 Mechanism-based treatment of low social RD includes 24 GABA-enhancers increase extracellular GABA, while posi- oxytocin, serotonin-norepinephrine reuptake inhibitors - SNRIs tive allosteric modulators change the conformation of GABA (desvenlafaxine, milnacipran, levo-milnacipran), norepinephrine A receptors (benzodiazepines, barbiturates, alcohol) and have reuptake inhibitors -NRIs (atomoxetine), MAOIs, psychosti- unreliable effects on aggression. mulants, and opioids (buprenorphine); (Svrakic et al. in prep.).

14 Dragan Svrakic, Mirjana Divac-Jovanovic & Naazia Azhar: AN INTEGRATIVE MODEL AND DYNAMIC NOSOLOGY OF PERSONALITY DISORDER: PART 2: SYMPTOM-BASED PHARMACOTHERAPY Psychiatria Danubina, 2019; Vol. 31, No. 1, pp 2-17

Metacognitive26 and mentalization based psychotherapy effect profile in comparison with typical antipsychotics. aiming to enhance one’s appreciation for his or her own In addition to antipsychotic effects, they also have and other people’s mental dynamisms are also indicated impressive antidepressant, antimanic, mood- stabilizing, for individuals with schizoid personality disorder, mainly and anxiolytic effects, likely reflecting multiple modes as the groundwork for reconstructive psychotherapy of of action and/ or functional overlap among brain fragmentation. networks involved in mood and cognition.

Symptom domain IV: Cognitive-Perceptual Clozapine and aripiprazole stand out Distortion and Psychotic Symptoms in the group of atypicals As discussed, this domain includes brief reactive Clozapine, to date the most effective medication psychoses as well as “soft” cognitive distortions, not- for positive, negative, and disorganization symptoms ably loose and biased cognition. Symptom-based medi- of Schizophrenia, is being increasingly used off label, cations are listed in Table 1. Risperidone is the most fre- to treat refractory depression, atypical depression, bi- quently used agent. Stress reduction is highly important polar disorder, anorexia, severe anxiety disorders, and as brief reactive psychoses typically occur in the context personality disorder, among others. The complex phar- of acute stress or personal crisis. Experience of stress macodynamic profile of clozapine may in part explain can be reduced by medication (“chemical suppression”), such wide spectrum effectiveness, which could be re- such as mood stabilizers (esp. valproate), antidepres- lated to either multiple specific mechanisms or a com- sants (e.g., mirtazapine), SGPs (aripirazole), GABA- bination of those. In addition to serotonergic (5- HT2A, enhancing anxiolytics (pregabalin), or positive allosteric 5- HT1A) and dopaminergic antagonism (mostly at D4 GABA A modulators (benzodiazepines). For example, receptors), clozapine is also a histone deacetylase alprazolam was shown to improve paranoia in border- (HDAC) inhibitor, thereby mediating epigenetic in- line individuals, presumably due to anxiolytic anti-stress crease in GABA production and GABA modulation of effects. Short-term use of benzodiazepines for perso- cortical pyramidal neurons, an effect believed to im- nality disorder increases the risk of behavior disin- prove cognitive processing and top-down cortical hibition and aggression, while long-term use increases control of subcortical functions. Also, clozapine is the risk of overuse. If prescribed, benzodiazepines believed to stimulate the synthesis of GABAergic should be monitored for abuse and used only short term neurosteroids, an effect that may explain its efficacy until the reactive psychosis is resolved. Alternative not only in psychosis but also in chronic anxiety and approaches to reduce stress include better coping skills, vulnerability to stress. By yet another mechanism, achieved in psychotherapy and meditation. clozapine blocks glycine transport, an effect that may enhance NMDA neurotransmission (Javitt et al. 2005) FINAL COMMENT and perhaps facilitate neuroplasticity and new lear- ning. In non-psychotic syndromes, clozapine is used at The second generation atypicals have low dose (25-100 mg/day, BID dosing), while its transformed pharmacotherapy plasma levels are kept within the low-to-medium range of non-psychotic syndromes (100-250 ng/mL)27. Clozapine is highly protein bound, Drawing from the dopamine hypothesis of psycho- hence plasma levels are monitored to ensure its sis, the group of first generation antipsychotics (aka presence in the plasma in its free, active form (the “typicals”) evolved from low-potency, sedating com- levels are used to guide the dosing). Clozapine – norclozapine ratio is kept at 2:1 at least, to avoid the pounds in the 1950s (e.g., chlorpromazine) to potent 28 D2 antagonists in the 1970s (e.g., haloperidol). These cardiac and hematologic side effects of norclozapine . drugs are primarily used to treat the positive symptoms Aripiprazole, originally marketed as an antipsychotic, of psychosis, such as delusions and hallucinations. is now more frequently used for other indications, such Administered to nonpsychotic individuals with per- as bipolar disorder, major depression, dysthymia, im- sonality or mood problems, typical antipsychotics have pulsive aggression, and trait anxiety in individuals with no desired specific effects but a plethora of undesired and without personality disorder, either as monotherapy effects, including irreversible tardive dyskinesia. or as an augmentation strategy. Aripiprazole is fre- A number of second generation agents - SGPs (aka quently referred to as a “third- generation” psychotropic “atypicals”) have been developed with multiple modes to illustrate its unique action profile which has been of pharmacodynamic actions, primarily targeting but not dubbed a “biased ligand” or “smart” pharmacological limited to DA and 5-HT neurotransmission. SGPs cause agent working at D2 and possibly D3 dopaminergic less sedation and have a much more favorable side- 27 Higher levels cca. 300-400 ng/ml are required to treat psychosis 26 Metacognition refers to the human capacity to be aware of 28 Many undesired effects can be minimized by careful clinical and control one's own thoughts and internal mental processes. and laboratory monitoring

15 Dragan Svrakic, Mirjana Divac-Jovanovic & Naazia Azhar: AN INTEGRATIVE MODEL AND DYNAMIC NOSOLOGY OF PERSONALITY DISORDER: PART 2: SYMPTOM-BASED PHARMACOTHERAPY Psychiatria Danubina, 2019; Vol. 31, No. 1, pp 2-17 receptors. It can act as a full antagonist, partial anta- 6. Comai S, Tau M, Pavlovic Z, et al.: The psychophar- gonist, and partial agonist at D2/D3 receptors. The type macology of aggressive behavior: A translational ap- of action is determined by local DA levels, cell type, proach part 2: Clinical studies using atypical anti- and functional and signaling status of the target cells. psychotics, anticonvulsants, and lithium. Journal of Clinical Psychopharmacology 2012b; 32:237-260 Aripiprazole is also a partial 5- HT1A agonist and a full 7. de Bartolomeis A, Tomasetti C, Iasevoli F: Update on the 5- HT2A antagonist, and it has NMDA, histaminic, and mechanism of action of aripiprazole: Translational adrenergic activity. 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Correspondence: Professor Dragan Svrakic, MD, PhD Department of Psychiatry, VA medical center St Louis, Washington University School of Medicine St Louis, MO, USA E-mail: [email protected]