Accepted Manuscript Childhood attachment and schizophrenia: the “attachment–developmental-cognitive” (ADC) hypothesis Ravi Philip Rajkumar PII: DOI: Reference:
S0306-9877(14)00221-7 http://dx.doi.org/10.1016/j.mehy.2014.05.017 YMEHY 7616
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
23 October 2013 24 May 2014
Please cite this article as: R.P. Rajkumar, Childhood attachment and schizophrenia: the “attachment–developmentalcognitive” (ADC) hypothesis, Medical Hypotheses (2014), doi: http://dx.doi.org/10.1016/j.mehy.2014.05.017
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Title: Childhood attachment and schizophrenia: the “attachment–developmentalcognitive” (ADC) hypothesis Ravi Philip Rajkumar, MD* * Associate Professor, Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India Address for correspondence: Ravi Philip Rajkumar Department of Psychiatry, JIPMER Dhanvantari Nagar, Pondicherry – 605 006, India Telephone number: 0091 9884713673 E-mail: [email protected] Sources of funding for the current work: None.
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Abstract: Schizophrenia is a complex psychiatric syndrome whose exact causes remain unclear. However, current scientific consensus has highlighted the importance of neurodevelopmental and neurocognitive processes in the development of schizophrenic symptoms. Research over the past three decades, motivated by the findings of the World Health Organization’s large-scale studies, has highlighted the importance of psychosocial adversities – including childhood abuse and neglect – in this disorder. In this paper, I propose a hypothesis based on John Bowlby’s framework of attachment theory, which I have termed the attachment-developmental-cognitive (ADC) hypothesis. The ADC hypothesis integrates recent developments related to (1) existing models of schizophrenia, (2) studies examining the effect of attachment on brain biology and cognitive development, and (3) various known facts about the course and outcome of this disorder. In doing so, it explains how disturbed childhood attachment leads to core psychological and neurochemical abnormalities which are implicated in the genesis of schizophrenia and also affect its outcome. The ADC hypothesis compasses and expands on earlier formulations, such as the “social defeat” and “traumagenic” models, and has important implications regarding the prevention and treatment of schizophrenia. Ways of testing and refining this hypothesis are outlined as avenues for future research. Though provisional, the ADC hypothesis is entirely consistent with both biological and psychosocial research into the origins of schizophrenia.
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Introduction: what causes schizophrenia? Schizophrenia is a complex psychiatric syndrome which has been reported across a wide range of countries and cultures, though its incidence varies according to region (1). The symptoms of schizophrenia are diverse, including delusions and hallucinations (positive or “reality distortion” symptoms), disturbances in the organization of behaviour and language (disorganization) and deficits in social and occupational functioning as well as cognition (negative or “psychomotor poverty” symptoms) (2, 3). This condition has generally been associated with a chronic course and persistent disability, though this is not invariable. The causes of schizophrenia remain obscure, though many clues have been obtained from epidemiological, pharmacological and biological research. In the earlier half of the last century, models based on family pathology, such as the concept of the “schizophrenogenic mother”, gained popularity. Though they had little empirical support, such models effectively stigmatized the parents of those suffering from schizophrenia, and strongly influenced psychotherapeutic practice (4, 5). Partly in reaction to this, the contemporary or “mainstream” model of schizophrenia has eschewed any references to familial factors and is firmly grounded in biological explanations; schizophrenia is seen as a neurodevelopmental disorder with a strong genetic component (6, 7). Despite its widespread acceptance, this model has little to say about the strong relationship between psychosocial factors and schizophrenia, and is therefore incomplete in a sense. Psychosocial theories of schizophrenia and the “DOSMD challenge”
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In the second half of the last century, the World Health Organization conducted two landmark studies which examined the long-term outcome of schizophrenia: the International Pilot Study of Schizophrenia (IPSS) (8,9) and the Determinants of the Outcome of Severe Mental Disorders (DOSMD) study (10). A consistent result across both these studies was that the outcome of schizophrenia was generally more favourable in “developing” countries, such as India and Nigeria, than in “developed” countries . This finding, though initially surprising, has now become something of a dogma in the schizophrenia literature, and has been described by some authors as “the most significant result in cross-cultural psychiatric research” (11). Reviewing the results of the DOSMD study, the original authors concluded that “culture” probably had an important effect on the outcome of schizophrenia, though they did not elaborate on this point (10). Subsequent authors have pointed to particular aspects of culture in “developing” countries, such as extended family support, or less negative attitudes towards the mentally ill; however, none of these has been conclusively shown to be the mechanism that accounts for the IPSS and DOSMD findings. Reflecting on this, Edgerton and Cohen coined the phrase “the DOSMD challenge” to refer to this unanswered question: to avoid falling into a “black box” explanation, what are the specific cultural factors that account for the DOSMD results? (12) In recent times, the notion that the outcome of schizophrenia is better in developing countries has been called into question. This critique has been driven by evidence from other studies, showing that the outcome of schizophrenia in “developing” countries may not be as favourable as it was once believed to be (13, 14). Interestingly, in parallel with
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this answer to the “DOSMD challenge”, there has been a resurgence of interest in the psychosocial determinants of schizophrenia, particularly in European countries. The findings of this research can be broadly divided into two categories:
1. Studies focusing on social adversities, such as poverty, discrimination and social deprivation (15, 16, 17). These studies, based on the often-replicated finding that ethnic minority migrants to “developed” countries have a higher risk of schizophrenia (18), have led to the suggestion that social defeat may be a final common pathway through which social disadvantage can lead to psychosis. This hypothesis was first coherently expressed in the literature by Selten and Cantor-Graae (19). 2. Studies examining the relationship between early childhood adversity – such as physical or sexual abuse – and schizophrenia (20, 21). These studies have led to the traumagenic neurodevelopmental model of schizophrenia (22), which postulates that childhood abuse or neglect can cause structural and functional changes in the developing brain, leading to schizophrenia later in life. These two theories are not mutually exclusive: for example, some studies have found that parental separations were more common in those individuals who later developed schizophrenia (20, 23), suggesting that social adversity can and does translate to individual childhood adversity in some cases. A point of interest here is that the “social defeat” hypothesis, though supported by epidemiological and biological research, does not adequately answer the “DOSMD challenge”. As Burns (24) has pointed out, social adversity, inequality and poverty are
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extremely common in “developing” countries, and ought to exert a deleterious rather than a protective effect on schizophrenia. This being the case, is it possible that explanations of the second type may yield better results? In this paper, I present a hypothesis that links early childhood experiences with the onset and outcome of schizophrenia. This model provides explanations of several intriguing findings in the schizophrenia literature, including the DOSMD challenge. Attachment theory: then and now Attachment theory, as initially elaborated by John Bowlby in Attachment and Loss (25, 26, 27), is a developmental theory which explains healthy childhood development – as well as psychopathology – on the basis of the phenomenon of attachment. According to Bowlby, attachment to a significant figure – usually a parent – is a fundamental biological mechanism that has evolved to protect the young of a species from predators (25). However, this is not the only function of an attachment bond. Attachment provides a child with the inputs from which she constructs internal representations (“working models”, to use Bowlby’s own term) of significant others, as well as of herself (25, 27). This notion, though purely theoretical when it was first proposed, has now received significant support from recent developments in neurobiology, which have shown that the human brain possess neurons (mirror neurons) capable of representing the actions of others. A network of mirror neurons could serve as a neural substrate for eventual models of the self, others, and the distinctions between them (28, 29, 30). Moreover, attachment bonds also play a crucial role in the growing child’s ability to make inferences about the emotions and states of mind of others – an ability known as
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“mentalization” or “theory of mind” (31, 32, 33). The disruption of an attachment bond leads to a variety of responses in the child, beginning with anger and anxiety, proceeding through depression, and eventually leading to a state of detachment (26). These phenomena may continue to be present in adult life, though in a concealed or modified form (26, 27). Though Bowlby’s original framework mainly addressed conditions such as depression and anxiety (26, 27), the above discussion shows that it is of potentially great relevance to schizophrenia as well. In the next section, I consider recent evidence that provides a strong theoretical basis for a link between attachment and existing neurocognitive and neurodevelopmental models of schizophrenia. Evidence in support of a role for attachment in schizophrenia Schizophrenia is now conceptualized as a neurodevelopmental disorder, which means that factors influencing the development of the brain during childhood and adolescence – which include not just severe forms of trauma, but the threatened or actual disruption of an attachment bond and even subtler forms of “insecure attachment” – must be given their due importance. Incidents such as physical or sexual abuse may not only be pathogenic in themselves, but may also be markers of more profound or long-lasting deficits in attachment. According to the neurodevelopmental model, insults to the developing brain lead to abnormalities in neural connectivity, which predispose an individual to the development of schizophrenia when exposed to stressors in adolescence or adulthood. These insults
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are often conceptualized either in terms of genetic abnormalities, or of perinatal insults such as infection. However, there is evidence that deficits in attachment can also cause functional abnormalities in the development and maturation of key brain circuits (34, 35). While the most striking evidence of these abnormalities is seen in cases of gross neglect (36), it is likely that even lesser forms of disrupted attachment, such as prolonged separations, can have a deleterious effect on the development of key brain pathways. Current neurocognitive models of schizophrenia stress the key role of two sets of psychological phenomena: 1) negative attributions related to the self and others, and 2) deficits in “theory of mind” skills (37, 38). Both these core deficits may have their roots in disruptions or deviations in attachment during the first decade of life, as discussed above (30, 31, 32). There is ample evidence that adequate attachment to parental figures is important for the development of certain aspects of “theory of mind” abilities. Moreover, attachment styles to parental figures strongly influence adult patterns of attachment, including beliefs about the self and about the likely responses of others. Such beliefs influence not only the formation of delusions, but the way in which a patient is likely to relate to others (39), leading to an impaired ability to seek support or maintain interpersonal relationships. Ultimately, therefore, disturbed attachment can potentially influence not only the development of psychosis, but its outcome. The hypothesis The hypothesis proposed here – which I have termed the “attachment-developmentalcognitive” (ADC) hypothesis of schizophrenia – postulates that disturbances in
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childhood attachment, including neglect and abuse, lead to deficits in neural representation of the self and others , impaired “theory of mind” skill, and sensitization of the mesolimbic dopamine pathway, which is relevant to positive symptom formation (40). Thus, such an individual is not only “sensitized” to stress (41), but has diminished capacities to respond to it either cognitively or emotionally. This would lead, according to cognitive models, to the development of delusions, hallucinations and passivity phenomena, as well as impaired interpersonal relationships. Through these pathways, disturbed attachment can influence not only the risk of developing schizophrenia, but its long-term course and prognosis. This does not rule out the possibility of genetic, biochemical, or neurophysiological factors being involved – as Bowlby himself pointed out with reference to depression (27). Nor does it require that attachment disturbances “cause” schizophrenia, which is a complex syndrome – or group of syndromes – and, as such, is unlikely to have a single cause. This hypothesis makes no simple assumptions of linear causation; instead, it brings a neglected aspect of human development to the fore, and uses it to explain several aspects of the existing literature on schizophrenia. Findings explained by this hypothesis The advantage of this hypothesis is that it incorporates, and extends, the traumagenic and neurodevelopmental models that represent the cutting edge of psychological and biological research into the causes of schizophrenia. In particular, the attachmentneurodevelopmental hypothesis explains:
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1. The association between schizophrenia and not only abuse and neglect (21, 42), but parental separation as well (20, 23), as all these could lead to the consequences described above. 2. The documented occurrence of deficits in “theory of mind” (43) and emotion recognition (44) in patients with schizophrenia; this is consistent with the evidence presented earlier, based on work in healthy children, which shows that attachment is crucial to the development of these skills. 3. The finding that adult patients with schizophrenia frequently have insecure adult attachment styles, either anxious or avoidant (39, 45); this would be a direct consequence of their adverse childhood experiences, and may also play a role in the maintenance of symptoms such as delusions and social avoidance (37). 4. The relationship between high levels of parental “expressed emotion” and relapse in schizophrenia (46); these provide a clue to possible aberrations in early attachment, while remaining consistent with the finding that disrupted attachment both affects social cognition and sensitizes the brain to respond to interpersonal stress in a manner that may lead to the development of psychotic symptoms (47). 5. The high rates of comorbid anxiety (48) and depression (49) in schizophrenia; these are predicted by Bowlby’s theory, which states that anxiety and depression are strongly linked to experiences of separation or loss in childhood.
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6. The “negative” symptoms of schizophrenia, such as reduced socialization; these could represent a modified form of the “detachment” response described by Bowlby in response to prolonged separation (26). Moreover, neurobiological research has shown that aberrant caregiving in childhood can alter the functioning of neuropeptides such as oxytocin and vasopressin (50, 51), which are important in regulating social behaviour (52); such alterations could represent a potential biochemical substrate for negative symptoms. 7. The relationship of schizophrenia to social defeat (4, 19). Disruption or deviance in early attachment bonds impairs the ability to form satisfactory interpersonal relationships in adolescence and adulthood, placing an individual at risk of social defeat, which places a further load on an already-sensitized dopamine pathway. 8. The relationship of schizophrenia to migration, including the puzzling phenomenon that rates of schizophrenia are higher in second-generation migrants (18), which one would not expect from a simple “cultural stress” model. It is likely that migrants have experienced adversities in their homelands during childhood, which might directly (e.g. parental loss) or indirectly (e.g. economic hardship or displacement leading to separations, or to parental stress and insecure attachment) have disturbed early attachment bonds. These disturbances would not only increase the risk of schizophrenia, but would also affect their own availability and ability as parents (23); in the absence of any sort of extended family support (see below), this would place their own children at an even higher risk.
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9. The finding that children born of unwanted pregnancies appear to have an elevated risk of schizophrenia (53). This has been conceptualized in terms of prenatal stress affecting foetal brain development, but it is entirely compatible with an attachment model. 10. The worse outcome of schizophrenia in patients who have experienced childhood adversity (54, 55), presumably due to the core neurobiological and psychological deficits engendered by impaired attachment. 11. The much-debated relationship between obstetric complications and schizophrenia (56). As with point 9 above, this has been viewed as evidence of a perinatal insult to the brain. However, adverse obstetric outcomes may also affect a mother’s response to her infant, as demonstrated in the case of women undergoing Caesarean sections (57). In addition to these findings, the attachment-neurodevelopmental model provides us with a possible answer to the DOSMD challenge. If social adversity is common in developing societies (14, 24), “low social adversity” cannot answer the DOSMD challenge. Instead, it is possible that influences earlier in the life cycle, particularly childhood experiences, could buffer the adverse consequences of a potential or actual social defeat. A tentative proposal as to how this might happen runs as follows: Patients from the “developing” countries of the IPSS and DOSMD studies, such as India, often lived in extended families, an arrangement which presumably dated from their childhood. In such a set-up, abandonment of a child by either parent is relatively rare, due to strict social sanctions. Children in extended families often form attachment bonds
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to other caregivers, particularly grandparents, uncles and aunts, which may play an important role in the development of “theory of mind” skills. Moreover, in the event of an inevitable separation from one or the other parent, either temporary or permanent, such caregivers often fulfill the role of a primary attachment figure, with two positive consequences: 1) a mitigation of the effects of separation from the parent, and 2) a reduced risk of being exposed to severe forms of adversity, such as childhood abuse or gross neglect. If the above explanation is true, it also explains why more recent studies in these “developing” settings have not replicated the IPSS and DOSMD findings. Over time, social circumstances in many of these countries have changed. Urbanization and internal migration have led to extended families becoming rarer, and nuclear families more common. High rates of abuse and neglect have been reported in children faced with such changes (58).Under such circumstances, the protective mechanism postulated above may no longer hold good (24), and outcomes in these countries may approximate those seen in the IPSS and DOSMD’s “developed” countries over time (14). Biological plausibility of the ADC hypothesis Though the points listed above are suggestive, a far more important question is whether the structural and functional brain changes caused by disrupted childhood attachment parallel the well-established changes seen in the brains of patients with schizophrenia; if this is not the case, then the hypothesis would have to be discarded. However, there
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are a number of striking similarities between these two sets of changes, as enumerated below (Table 1) (Insert Table 1 Here) Though the above evidence is entirely consistent with the hypothesis, it must be interpreted with caution, as many of the cited studies are confounded by factors such as age at assessment, gender, type of childhood adversity and psychiatric comorbidity. Further research on the neurobiological changes caused by disrupted childhood attachment, with and without abuse, would place these associations on a firmer footing. Testing and refining the ADC hypothesis The role of attachment in schizophrenia can be tested both retrospectively and prospectively. In the former case, patients with a diagnosis of schizophrenia can be interviewed with structured instruments to assess both early (parental) and current measures of attachment, and their relationship to variables such as age at onset, disease course, treatment response, symptom profile, and outcome. If the hypothesis proposed above is correct, we would expect a strong correlation to be found between measures or markers of disrupted childhood attachment and psychosis, as well as a negative effect of such disruptions on the outcome of schizophrenia. Prospective studies could examine both the general population and “high-risk” groups, such as adolescents with prodromal symptoms or “psychosis risk syndrome”; if the hypothesis is correct, we would find a higher “conversion rate” to psychosis in high-risk subjects who have experienced childhood adversity.
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Second, further evidence must be obtained regarding the impact of disturbed childhood attachment on the symptomatology and outcome of schizophrenia. There is already some evidence that childhood trauma is associated with more severe positive symptoms and more frequent suicide attempts in schizophrenia (71). Moreover, Rosenberg et al (54) found a relationship between childhood adversity and a variety of adverse outcomes in schizophrenia, including comorbid substance use and imprisonment. These findings, though supportive of the hypothesis, need to be replicated. Third, the interaction between attachment and other risk factors for schizophrenia, such as vulnerability genes, substance abuse and infection, needs to be examined. There is already some evidence for gene-environment effects with regard to adversity in general (72), but a specific interaction between attachment and other factors still requires demonstration. Finally, the model can be refined by examining three important questions: 1. Is there any critical threshold of adversity or separation that is specifically “pathogenic”? 2. Are there any specific kinds of adversity, such as neglect or physical abuse, that can disrupt the key psychological processes implicated in schizophrenia, or is there a general “class effect” for all kinds of disrupted attachment? 3. What are the factors that may play a role in protecting against the harmful effects of disrupted or deviant attachment?
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Limitations of the hypothesis The model proposed above is consistent with the neurocognitive and neurodevelopmental models of schizophrenia, is supported by existing literature, and extends the efforts of some authors (such as Read’s “traumagenic model”) to examine the relationship between childhood adversity and psychosis. It also provides an empirically valid theoretical framework – attachment theory – in which this relationship can be examined. However, the following limitations must be borne in mind: 1. Disturbed attachment has been linked to a wide variety of disorders, both in childhood and adulthood. Moreover, disturbed attachment is far more common than schizophrenia in the general population. We cannot be certain if the relationship to schizophrenia is causal, or if disturbed attachment is a general vulnerability factor that raises susceptibility to a variety of mental disorders, including anxiety and depression. In all probability, certain forms of disturbed attachment – which have the particular effects of interfering with theory of mind skills and attribution styles – will be found to have a link to schizophrenia, as mentioned in the previous section. Delineating these attachment patterns is the key task that future researchers in this area will face. 2. The verification of this hypothesis, if successful, should not lead to a simplistic assignment of blame to a patient’s parents, and more specifically to his mother. Disturbed attachment is a complex phenomenon, and is often transmitted intergenerationally; the transmission of abusive parenting across generations has also been demonstrated in animal models. Parents who have difficulty bonding
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with their children have often received sub-optimal care from their own parents or caregivers, and their difficulties are compounded by the very real stress of caring for a child with schizophrenia. Such parents require support and empathy, rather than the blanket condemnation they were subjected to under the old psychodynamic models. 3. The plausibility of this hypothesis should not lead to simplistic reasoning about disturbed attachment being “the cause” of schizophrenia. Schizophrenia is best understood as a complex syndrome rather than as a unitary disorder, and the relative importance of various factors in a given patient may vary. At this point in time, we cannot be certain if attachment is relevant in all patients with schizophrenia, or only in a specific sub-set of them. Implications of the hypothesis The ramifications of an attachment-based hypothesis for schizophrenia are considerable, and can be considered at three levels: preventive, therapeutic and translational. From a preventive point of view, the most immediate application of this model would be to children and adolescents who are considered to be at a high risk of developing schizophrenia, either genetically or on the basis of their symptoms. Family intervention in such patients, aimed at strengthening attachment bonds and modifying interactional patterns, may effectively prevent them from developing the full syndrome of schizophrenia. This contention has some support from a literature review which
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demonstrated that family interventions have a more robust effect on the outcome of early psychosis than cognitive-behavioural therapy (73). It is too early to say if largerscale social programmes, aimed at assisting parents and enabling them to provide better care to their children, would actually reduce the incidence of schizophrenia; however, this corollary to the hypothesis cannot be ruled out. From a therapeutic point of view, this hypothesis points to the need for adequate psychosocial interventions in patients with schizophrenia, rather than a one-sided dependence on pharmacotherapy. While pharmacological interventions are invaluable in controlling acute symptoms, attachment-informed psychotherapies may assist patients in acquiring theory of mind skills and modifying attributions, thereby improving their social and occupational functioning, weakening paranoid delusions, and reducing the risk of relapses. From a translational perspective, the consequences of disturbed attachment, as seen in the delusions and other symptoms of schizophrenia, would provide valuable insights into the exact mechanisms by which childhood attachment leads to the development of interactional styles, attributions, and mentalization skills. Such mechanisms could be studied at various levels – behavioural, neurophysiological, genetic, and biochemical – and could enrich our knowledge not only of schizophrenia, but of human attachment and social cognition in general.
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Conclusion The ADC hypothesis outlined above is provisional, and is clearly in need of further support from clinical and community research. Besides, it cannot be viewed as a unitary “theory of schizophrenia”. Despite this, an attachment-informed perspective on schizophrenia, as outlined in this hypothesis, is consistent with both biological and psychosocial models of this disorder, strengthens them, and explains their interrelationships. This property sets it apart from other theories of schizophrenia and allows it to stand as a companion to them, thereby deepening our understanding of the developmental pathways that have schizophrenia as their end-point. Conflicts of interest: None
References:
1. McGrath JJ, Susser ES. New directions in the epidemiology of schizophrenia. MJA 2009; 190: S7-S9. 2. Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones T, Frackowiak RS. Patterns of cerebral blood flow in schizophrenia. Br J Psychiatry 1992; 160: 179-186. 3. Goghari VM, Sponheim SR, MacDonald AW. The functional neuroanatomy of symptom dimensions in schizophrenia: a qualitative and quantitative review of a persistent question. Neurosci Biobehav Rev 2010; 34: 468-486.
20
4. Luhrmann TM. Social defeat and the culture of chronicity: or, why schizophrenia does so well over there and so badly here. Cult Med Psychiatry 2007; 31: 135172. 5. Harrington A. The fall of the schizophrenogenic mother. Lancet 2012; 379: 12921293. 6. Pantelis C, Yucel M, Wood SJ, McGorry PD, Velakoulis D. Early and late neurodevelopmental disturbances in schizophrenia and their functional consequences. Aust N Z J Psychiatry 2003; 37: 399-406. 7. Rapoport JL, Giedd JN, Gogtay N. Neurodevelopmental model of schizophrenia: update 2012. Mol Psychiatry 2012; 17: 1228-1238. 8. Sartorius N, Shapiro R, Jablensky A. The International Pilot Study of Schizophrenia. Schizophr Bull 1974; 11: 21-34. 9. Leff J, Sartorius N, Jablensky A, Korten A, Ernberg G. The International Pilot Study of Schizophrenia: five-year follow-up findings. Psychol Med 1992; 22: 131145. 10. Jablensky A, Sartorius N, Ernberg G et al. Schizophrenia: manifestations, incidence and course in different cultures. Psychol Med 1992; S20: 1-95. 11. Lin K-M, Kleinman A. Psychopathology and clinical course of schizophrenia: a cross-cultural perspective. Schizophr Bull 1988; 14: 555-567. 12. Edgerton RB, Cohen A. Culture and schizophrenia: the DOSMD challenge. Br J Psychiatry 1994; 164: 222-231. 13. Cohen A, Patel V, Thara R, Gureje O. Questioning an axiom: better prognosis for schizophrenia in the developing world? Schizophr Bull 2008; 34: 229-244.
21
14. Patel V, Cohen A, Thara R, Gureje O. Is the outcome of schizophrenia really better in developing countries? Rev Bras Psiquiatr 2006; 28: 149-152. 15. Bentall RP, Fernyhough C. Social predictors of psychotic experiences: specificity and psychological mechanisms. Schizophr Bull 2008; 34: 1012-1020. 16. Allardyce J, Boydell J. Review: the wider social environment and schizophrenia. Schizophr Bull 2006; 32: 592-598. 17. Veling W, Selten J-P, Susser E, Laan W, Mackenbach JP, Hoek HW. Discrimination and the incidence of psychotic disorders among ethnic minorities in the Netherlands. Int J Epidemiol 2007; 36: 761-768. 18. Cantor-Graae E, Selten J-P. Schizophrenia and migration: a meta-analysis and review. Am J Psychiatry 2005; 162: 12-24. 19. Selten J-P, Cantor-Graae E. Hypothesis: social defeat is a risk factor for schizophrenia? Br J Psychiatry 2007; 191 (S51): S9-S12. 20. Bebbington PE, Bhugra D, Brugha T et al. Psychosis, victimization and childhood disadvantage: evidence from the second British National Survey of Psychiatric Morbidity. Br J Psychiatry 2004; 185: 220-226. 21. Bendall S, Jackson HJ, Hulbert CA, McGorry PD. Childhood trauma and psychotic disorders: a systematic, critical review of the evidence. Schizophr Bull 2008; 34: 568-579. 22. Read J, Perry BD, Moskowitz A, Connolly J. The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model. Psychiatry 2001; 64: 319-345.
22
23. Morgan C, Kirkbride J, Leff J et al. Parental separation, loss and psychosis in different ethnic groups: a case-control study. Psychol Med 2007; 37: 495-503. 24. Burns J. Dispelling a myth: developing world poverty, inequality, violence and social fragmentation are not good for outcome in schizophrenia. Afr J Psychiatry 2009; 12: 200-205. 25. Bowlby J. Attachment and Loss. Volume 1: Attachment. London: Pimlico, Random House 1997. 26. Bowlby J. Attachment and Loss. Volume 2: Separation. London: Pimlico, Random House 1998. 27. Bowlby J. Attachment and Loss. Volume 3: Loss. London: Pimlico, Random House 1998. 28. Gallese V. The roots of empathy: the shared manifold hypothesis and the neural basis of intersubjectivity. Psychopathology 2003; 36: 171-180. 29. Meltzoff AN, Decety J. What imitation tells us about social cognition: a rapprochement between developmental psychology and cognitive neuroscience. Phil Trans R Soc Lond B 2003; 358: 491-500. 30. Fonagy P, Gergely G, Target M. The parent-infant dyad and the construction of the subjective self. J Child Psychol Psychiatry 2007; 48: 288-328. 31. Laible DJ, Thompson RA. Attachment and emotional understanding in preschool children. Dev Psychol 1998; 34: 1038-1045. 32. Ontai LL, Thompson RA. Patterns of attachment and maternal discourse effects on children’s emotion understanding from 3 to 5 years of age. Soc Development 2002; 11: 433-450.
23
33. Meins E, Fernyhough C, Russell J. Security of attachment as a predictor of symbolic and mentalising abilities: a longitudinal study. Soc Development 1998; 7: 1-24. 34. Schore AN. Attachment, affect regulation and the developing right brain: linking developmental neuroscience to pediatrics. Pediatrics Rev 2005; 26: 204-217. 35. Pruessner JC, Champagne F, Meaney MJ, Dagher A. Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using 11C-raclopride. J Neurosci 2004; 24: 2825-2831. 36. Chugani HT, Behen ME, Muzik O, Juhasz C, Nagy F, Chugani DC. Local brain functional activity following early deprivation: a study of postinstitutionalized Romanian orphans. Neuroimage 2001; 14: 1290-1301. 37. Garety PA, Kuipers E, Fowler D, Freeman D, Bebbington PE. A cognitive model of the positive symptoms of psychosis. Psychol Med 2001; 31: 189-195. 38. Garety PA, Bebbington P, Fowler D, Freeman D, Kuipers E. Implications for neurobiological research of cognitive models of psychosis: a theoretical paper. Psychol Med 2007; 37: 1377-1391. 39. Berry K, Barrowclough C, Wearden A. Attachment theory: a framework for understanding symptoms and interpersonal relationships in psychosis. Behav Res Therapy 2008; 46: 1275-1282. 40. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia : version III – the final common pathway. Schizophr Bull 2009; 35: 549-562.
24
41. Collip D, Myin-Germeyes I, van Os J. Does the concept of “sensitization” provide a plausible mechanism for the putative link between the environment and schizophrenia? Schizophr Bull 2008; 34: 220-225. 42. Varese F, Smeets F, Drukker M et al. Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr Bull 2012; 38: 661-671. 43. Brune M. “Theory of mind” in schizophrenia: a review of the literature. Schizophr Bull 2005; 31: 21-42. 44. Kohler CG, Walker JB, Martin EA, Healey KM, Moberg PJ. Facial emotion perception in schizophrenia: a meta-analytic review. Schizophr Bull 2010; 36: 1009-1019. 45. MacBeth A, Gumley A, Schwannauer M, Fisher R. Attachment states of mind, mentalization, and their correlates in a first-episode psychosis sample. Psychol Psychother 2011; 84: 42-57. 46. Butzlaff RL, Hooley JM. Expressed emotion and psychiatric relapse: a metaanalysis. Arch Gen Psychiatry 1998; 55: 547-552. 47. Rosenfarb IS, Nuechterlein KH, Goldstein MJ, Subotnik KL. Neurocognitive vulnerability, interpersonal criticism, and the emergence of unusual thinking by schizophrenic patients during family transactions. Arch Gen Psychiatry 2000; 57: 1174-1179. 48. Achim AM, Maziade M, Raymond E, Olivier D, Merette C, Roy M-A. How prevalent are anxiety disorders in schizophrenia? A meta-analysis and critical review on a significant association. Schizophr Bull 2011; 37: 811-821.
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49. Moller H-J. Occurrence and treatment of depressive comorbidity/cosyndromality in schizophrenic psychoses: conceptual and treatment issues. World J Biol Psychiatry 2005; 6: 247-263. 50. Tops M, Van Peer JM, Korf J, Wijers AA, Tucker DM. Anxiety, cortisol and attachment predict plasma oxytocin. Psychophysiology 2007; 44: 444-449. 51. Wismer Fries AB, Ziegler TE, Kurian JR, Jacoris S, Pollak SD. Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. PNAS 2005; 102: 17237-17240. 52. Ross HE, Young LJ. Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior. Front Neuroendocrinol 2009; 30: 534-547. 53. Myhrman A, Rantakallio P, Isohanni M, Jones P, Partanen U. Unwantedness of pregnancy and schizophrenia in the child. Br J Psychiatry 1996; 169: 637-640. 54. Rosenberg SD, Lu W, Mueser KT, Jankowski MK, Cournos F. Correlates of adverse childhood events among adults with schizophrenia spectrum disorders. Psychiatr Serv 2007; 58: 245-253. 55. Mueser KT, Rosenberg SD, Goodman LA, Trumbetta SL. Trauma, PTSD and the course of severe mental illness: an interactive model. Schizophr Res 2002; 53: 123-143. 56. Cannon M, Jones PB, Murray RM. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry 2002; 159: 1080-1092. 57. Swain JE, Tasgin E, Mayes LC, Feldman R, Constable RT, Leckman JF. Maternal brain response to own baby-cry is affected by cesarean section delivery. J Child Psychol Psychiatry 2008; 49: 1042-1052.
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58. Kacker L, Varadan S, Kumar P. Study on child abuse: India. New Delhi: Ministry of Women and Child Development, Government of India 2007. 59. De Bellis MD, Keshavan MS, Clark DB et al. Developmental traumatology part II: brain development. Biol Psychiatry 1999; 45: 1271-1284. 60. Carrion VG, Weems CF, Eliez S et al. Attenuation of frontal asymmetry in pediatric posttraumatic stress disorder. Biol Psychiatry 2001; 50: 943-951. 61. Keshavan MS, Tandon R, Boutros NN, Nasrallah HA. Schizophrenia, “just the facts”: what we know in 2008. Part 3: neurobiology. Schizophr Res 2008; 106: 89-107. 62. Belsky J, de Haan M. Annual research review: parenting and children's brain development: the end of the beginning. J Child Psychol Psychiatry 2011; 52: 409-428. 63. Dannlowski U, Stuhrmann A, Beutelmann V et al. Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biol Psychiatry 2012; 71: 286-293. 64. Choi J, Jeong B, Rohan ML, Polcari AM, Teicher MH. Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse. Biol Psychiatry 2009; 65: 227-234. 65. Kaufman J, Birmaher B, Perel J et al. Serotonergic functioning in depressed abused children: clinical and familial correlates. Biol Psychiatry 1998: 44: 973981. 66. Cowen PJ, Gadhvi H, Gosden B, Kolakowska T. Responses of prolactin and growth hormone to L-tryptophan infusion: effects in normal subjects and
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schizophrenic patients receiving neuroleptics. Psychopharmacol 1985: 86: 164169. 67. Twardosz S, Lutzker JR. Child maltreatment and the developing brain: a review of neuroscience perspectives. Aggress Violent Behav 2010; 15; 59-68. 68. Watts-English T, Fortson BL, Gibler N, Hooper SR, De Bellis MD. The psychobiology of maltreatment in childhood. J Soc Issues 2006; 62: 717-736. 69. Zhang XY, Zhou DF, Cao LY, Wu GY, Shen YC. Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics. Neuropsychopharmacol 2005; 30: 1532-1538. 70. Eaton WW, Byrne M, Ewald H et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 2006; 163: 521-528. 71. Ucok A, Bikmaz S. The effects of childhood trauma in patients with first-episode schizophrenia. Acta Psychiatr Scand 2007; 116: 371-377. 72. Van Winkel R, Stefanis NC, Myin-Germeys I. Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction. Schizophr Bull 2008; 34: 1095-1105. 73. Bird V, Premkumar P, Kendall T, Whittington C, Mitchell J, Kuipers E. Early intervention services, cognitive-behavioural therapy and family intervention in early psychosis: systematic review. Br J Psychiatry 2010; 197: 350-356.
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“Childhood attachment and schizophrenia: the “attachment–developmentalcognitive” (ADC) hypothesis”
Financial support: No extramural funding was provided for this work. Conflicts of interest: None.
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Table 1: Neurobiological similarities between disrupted childhood attachment and schizophrenia
Domain
Changes observed
Remarks
Brain structure 1. Whole brain volume
2. Ventricular enlargement
3. Hippocampal volume
Reduced in maltreated Also seen in drug-naive children; earlier exposures patients with schizophrenia seem to have greater effects (61) (59, 60) Frequently reported in Some studies have found an patients with schizophrenia (61) association between ventricular enlargement and early childhood abuse (62)
Reduced both in children who have experienced trauma (62) and in healthy adults who have experienced childhood maltreatment (63) 4. White matter changes Reduced white matter tract integrity has been reported in adults exposed to verbal abuse during childhood (64)
Hippocampal volume, particularly gray matter volume, reduced in schizophrenia (61)
Similar changes have been reported in schizophrenia (61)
Neurotransmitter release 1. Dopamine transmission
Lower maternal care associated with increased dopamine release in response to stress (35)
2. Serotonin transmission
Increased prolactin response to 5-hydroxytryptophan seen
Potentially relevant for the formation of delusions (40)
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in depressed children with a Similar changes seen in history of neglect (65) drug-naive patients with schizophrenia (66)
Neuroendocrine changes Hypercortisolemia and overactivation of the hypothalamo-pituitaryadrenal (HPA) axis
Has been found as a Often found in patients with consequence of child neglect schizophrena; may reflect a and abuse in several studies stress response (61) (62, 67)
Others Immune dysregulation and pro-inflammatory activity
Elevated auto-antibody titres have been reported in abused girls by some researchers (68)
Recent evidence of immune and inflammatory dysfunction, including autoimmunity, in schizophrenia (69)
S0306-9877(14)00221-7 http://dx.doi.org/10.1016/j.mehy.2014.05.017 YMEHY 7616
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
23 October 2013 24 May 2014
Please cite this article as: R.P. Rajkumar, Childhood attachment and schizophrenia: the “attachment–developmentalcognitive” (ADC) hypothesis, Medical Hypotheses (2014), doi: http://dx.doi.org/10.1016/j.mehy.2014.05.017
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Title: Childhood attachment and schizophrenia: the “attachment–developmentalcognitive” (ADC) hypothesis Ravi Philip Rajkumar, MD* * Associate Professor, Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India Address for correspondence: Ravi Philip Rajkumar Department of Psychiatry, JIPMER Dhanvantari Nagar, Pondicherry – 605 006, India Telephone number: 0091 9884713673 E-mail: [email protected] Sources of funding for the current work: None.
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Abstract: Schizophrenia is a complex psychiatric syndrome whose exact causes remain unclear. However, current scientific consensus has highlighted the importance of neurodevelopmental and neurocognitive processes in the development of schizophrenic symptoms. Research over the past three decades, motivated by the findings of the World Health Organization’s large-scale studies, has highlighted the importance of psychosocial adversities – including childhood abuse and neglect – in this disorder. In this paper, I propose a hypothesis based on John Bowlby’s framework of attachment theory, which I have termed the attachment-developmental-cognitive (ADC) hypothesis. The ADC hypothesis integrates recent developments related to (1) existing models of schizophrenia, (2) studies examining the effect of attachment on brain biology and cognitive development, and (3) various known facts about the course and outcome of this disorder. In doing so, it explains how disturbed childhood attachment leads to core psychological and neurochemical abnormalities which are implicated in the genesis of schizophrenia and also affect its outcome. The ADC hypothesis compasses and expands on earlier formulations, such as the “social defeat” and “traumagenic” models, and has important implications regarding the prevention and treatment of schizophrenia. Ways of testing and refining this hypothesis are outlined as avenues for future research. Though provisional, the ADC hypothesis is entirely consistent with both biological and psychosocial research into the origins of schizophrenia.
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Introduction: what causes schizophrenia? Schizophrenia is a complex psychiatric syndrome which has been reported across a wide range of countries and cultures, though its incidence varies according to region (1). The symptoms of schizophrenia are diverse, including delusions and hallucinations (positive or “reality distortion” symptoms), disturbances in the organization of behaviour and language (disorganization) and deficits in social and occupational functioning as well as cognition (negative or “psychomotor poverty” symptoms) (2, 3). This condition has generally been associated with a chronic course and persistent disability, though this is not invariable. The causes of schizophrenia remain obscure, though many clues have been obtained from epidemiological, pharmacological and biological research. In the earlier half of the last century, models based on family pathology, such as the concept of the “schizophrenogenic mother”, gained popularity. Though they had little empirical support, such models effectively stigmatized the parents of those suffering from schizophrenia, and strongly influenced psychotherapeutic practice (4, 5). Partly in reaction to this, the contemporary or “mainstream” model of schizophrenia has eschewed any references to familial factors and is firmly grounded in biological explanations; schizophrenia is seen as a neurodevelopmental disorder with a strong genetic component (6, 7). Despite its widespread acceptance, this model has little to say about the strong relationship between psychosocial factors and schizophrenia, and is therefore incomplete in a sense. Psychosocial theories of schizophrenia and the “DOSMD challenge”
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In the second half of the last century, the World Health Organization conducted two landmark studies which examined the long-term outcome of schizophrenia: the International Pilot Study of Schizophrenia (IPSS) (8,9) and the Determinants of the Outcome of Severe Mental Disorders (DOSMD) study (10). A consistent result across both these studies was that the outcome of schizophrenia was generally more favourable in “developing” countries, such as India and Nigeria, than in “developed” countries . This finding, though initially surprising, has now become something of a dogma in the schizophrenia literature, and has been described by some authors as “the most significant result in cross-cultural psychiatric research” (11). Reviewing the results of the DOSMD study, the original authors concluded that “culture” probably had an important effect on the outcome of schizophrenia, though they did not elaborate on this point (10). Subsequent authors have pointed to particular aspects of culture in “developing” countries, such as extended family support, or less negative attitudes towards the mentally ill; however, none of these has been conclusively shown to be the mechanism that accounts for the IPSS and DOSMD findings. Reflecting on this, Edgerton and Cohen coined the phrase “the DOSMD challenge” to refer to this unanswered question: to avoid falling into a “black box” explanation, what are the specific cultural factors that account for the DOSMD results? (12) In recent times, the notion that the outcome of schizophrenia is better in developing countries has been called into question. This critique has been driven by evidence from other studies, showing that the outcome of schizophrenia in “developing” countries may not be as favourable as it was once believed to be (13, 14). Interestingly, in parallel with
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this answer to the “DOSMD challenge”, there has been a resurgence of interest in the psychosocial determinants of schizophrenia, particularly in European countries. The findings of this research can be broadly divided into two categories:
1. Studies focusing on social adversities, such as poverty, discrimination and social deprivation (15, 16, 17). These studies, based on the often-replicated finding that ethnic minority migrants to “developed” countries have a higher risk of schizophrenia (18), have led to the suggestion that social defeat may be a final common pathway through which social disadvantage can lead to psychosis. This hypothesis was first coherently expressed in the literature by Selten and Cantor-Graae (19). 2. Studies examining the relationship between early childhood adversity – such as physical or sexual abuse – and schizophrenia (20, 21). These studies have led to the traumagenic neurodevelopmental model of schizophrenia (22), which postulates that childhood abuse or neglect can cause structural and functional changes in the developing brain, leading to schizophrenia later in life. These two theories are not mutually exclusive: for example, some studies have found that parental separations were more common in those individuals who later developed schizophrenia (20, 23), suggesting that social adversity can and does translate to individual childhood adversity in some cases. A point of interest here is that the “social defeat” hypothesis, though supported by epidemiological and biological research, does not adequately answer the “DOSMD challenge”. As Burns (24) has pointed out, social adversity, inequality and poverty are
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extremely common in “developing” countries, and ought to exert a deleterious rather than a protective effect on schizophrenia. This being the case, is it possible that explanations of the second type may yield better results? In this paper, I present a hypothesis that links early childhood experiences with the onset and outcome of schizophrenia. This model provides explanations of several intriguing findings in the schizophrenia literature, including the DOSMD challenge. Attachment theory: then and now Attachment theory, as initially elaborated by John Bowlby in Attachment and Loss (25, 26, 27), is a developmental theory which explains healthy childhood development – as well as psychopathology – on the basis of the phenomenon of attachment. According to Bowlby, attachment to a significant figure – usually a parent – is a fundamental biological mechanism that has evolved to protect the young of a species from predators (25). However, this is not the only function of an attachment bond. Attachment provides a child with the inputs from which she constructs internal representations (“working models”, to use Bowlby’s own term) of significant others, as well as of herself (25, 27). This notion, though purely theoretical when it was first proposed, has now received significant support from recent developments in neurobiology, which have shown that the human brain possess neurons (mirror neurons) capable of representing the actions of others. A network of mirror neurons could serve as a neural substrate for eventual models of the self, others, and the distinctions between them (28, 29, 30). Moreover, attachment bonds also play a crucial role in the growing child’s ability to make inferences about the emotions and states of mind of others – an ability known as
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“mentalization” or “theory of mind” (31, 32, 33). The disruption of an attachment bond leads to a variety of responses in the child, beginning with anger and anxiety, proceeding through depression, and eventually leading to a state of detachment (26). These phenomena may continue to be present in adult life, though in a concealed or modified form (26, 27). Though Bowlby’s original framework mainly addressed conditions such as depression and anxiety (26, 27), the above discussion shows that it is of potentially great relevance to schizophrenia as well. In the next section, I consider recent evidence that provides a strong theoretical basis for a link between attachment and existing neurocognitive and neurodevelopmental models of schizophrenia. Evidence in support of a role for attachment in schizophrenia Schizophrenia is now conceptualized as a neurodevelopmental disorder, which means that factors influencing the development of the brain during childhood and adolescence – which include not just severe forms of trauma, but the threatened or actual disruption of an attachment bond and even subtler forms of “insecure attachment” – must be given their due importance. Incidents such as physical or sexual abuse may not only be pathogenic in themselves, but may also be markers of more profound or long-lasting deficits in attachment. According to the neurodevelopmental model, insults to the developing brain lead to abnormalities in neural connectivity, which predispose an individual to the development of schizophrenia when exposed to stressors in adolescence or adulthood. These insults
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are often conceptualized either in terms of genetic abnormalities, or of perinatal insults such as infection. However, there is evidence that deficits in attachment can also cause functional abnormalities in the development and maturation of key brain circuits (34, 35). While the most striking evidence of these abnormalities is seen in cases of gross neglect (36), it is likely that even lesser forms of disrupted attachment, such as prolonged separations, can have a deleterious effect on the development of key brain pathways. Current neurocognitive models of schizophrenia stress the key role of two sets of psychological phenomena: 1) negative attributions related to the self and others, and 2) deficits in “theory of mind” skills (37, 38). Both these core deficits may have their roots in disruptions or deviations in attachment during the first decade of life, as discussed above (30, 31, 32). There is ample evidence that adequate attachment to parental figures is important for the development of certain aspects of “theory of mind” abilities. Moreover, attachment styles to parental figures strongly influence adult patterns of attachment, including beliefs about the self and about the likely responses of others. Such beliefs influence not only the formation of delusions, but the way in which a patient is likely to relate to others (39), leading to an impaired ability to seek support or maintain interpersonal relationships. Ultimately, therefore, disturbed attachment can potentially influence not only the development of psychosis, but its outcome. The hypothesis The hypothesis proposed here – which I have termed the “attachment-developmentalcognitive” (ADC) hypothesis of schizophrenia – postulates that disturbances in
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childhood attachment, including neglect and abuse, lead to deficits in neural representation of the self and others , impaired “theory of mind” skill, and sensitization of the mesolimbic dopamine pathway, which is relevant to positive symptom formation (40). Thus, such an individual is not only “sensitized” to stress (41), but has diminished capacities to respond to it either cognitively or emotionally. This would lead, according to cognitive models, to the development of delusions, hallucinations and passivity phenomena, as well as impaired interpersonal relationships. Through these pathways, disturbed attachment can influence not only the risk of developing schizophrenia, but its long-term course and prognosis. This does not rule out the possibility of genetic, biochemical, or neurophysiological factors being involved – as Bowlby himself pointed out with reference to depression (27). Nor does it require that attachment disturbances “cause” schizophrenia, which is a complex syndrome – or group of syndromes – and, as such, is unlikely to have a single cause. This hypothesis makes no simple assumptions of linear causation; instead, it brings a neglected aspect of human development to the fore, and uses it to explain several aspects of the existing literature on schizophrenia. Findings explained by this hypothesis The advantage of this hypothesis is that it incorporates, and extends, the traumagenic and neurodevelopmental models that represent the cutting edge of psychological and biological research into the causes of schizophrenia. In particular, the attachmentneurodevelopmental hypothesis explains:
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1. The association between schizophrenia and not only abuse and neglect (21, 42), but parental separation as well (20, 23), as all these could lead to the consequences described above. 2. The documented occurrence of deficits in “theory of mind” (43) and emotion recognition (44) in patients with schizophrenia; this is consistent with the evidence presented earlier, based on work in healthy children, which shows that attachment is crucial to the development of these skills. 3. The finding that adult patients with schizophrenia frequently have insecure adult attachment styles, either anxious or avoidant (39, 45); this would be a direct consequence of their adverse childhood experiences, and may also play a role in the maintenance of symptoms such as delusions and social avoidance (37). 4. The relationship between high levels of parental “expressed emotion” and relapse in schizophrenia (46); these provide a clue to possible aberrations in early attachment, while remaining consistent with the finding that disrupted attachment both affects social cognition and sensitizes the brain to respond to interpersonal stress in a manner that may lead to the development of psychotic symptoms (47). 5. The high rates of comorbid anxiety (48) and depression (49) in schizophrenia; these are predicted by Bowlby’s theory, which states that anxiety and depression are strongly linked to experiences of separation or loss in childhood.
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6. The “negative” symptoms of schizophrenia, such as reduced socialization; these could represent a modified form of the “detachment” response described by Bowlby in response to prolonged separation (26). Moreover, neurobiological research has shown that aberrant caregiving in childhood can alter the functioning of neuropeptides such as oxytocin and vasopressin (50, 51), which are important in regulating social behaviour (52); such alterations could represent a potential biochemical substrate for negative symptoms. 7. The relationship of schizophrenia to social defeat (4, 19). Disruption or deviance in early attachment bonds impairs the ability to form satisfactory interpersonal relationships in adolescence and adulthood, placing an individual at risk of social defeat, which places a further load on an already-sensitized dopamine pathway. 8. The relationship of schizophrenia to migration, including the puzzling phenomenon that rates of schizophrenia are higher in second-generation migrants (18), which one would not expect from a simple “cultural stress” model. It is likely that migrants have experienced adversities in their homelands during childhood, which might directly (e.g. parental loss) or indirectly (e.g. economic hardship or displacement leading to separations, or to parental stress and insecure attachment) have disturbed early attachment bonds. These disturbances would not only increase the risk of schizophrenia, but would also affect their own availability and ability as parents (23); in the absence of any sort of extended family support (see below), this would place their own children at an even higher risk.
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9. The finding that children born of unwanted pregnancies appear to have an elevated risk of schizophrenia (53). This has been conceptualized in terms of prenatal stress affecting foetal brain development, but it is entirely compatible with an attachment model. 10. The worse outcome of schizophrenia in patients who have experienced childhood adversity (54, 55), presumably due to the core neurobiological and psychological deficits engendered by impaired attachment. 11. The much-debated relationship between obstetric complications and schizophrenia (56). As with point 9 above, this has been viewed as evidence of a perinatal insult to the brain. However, adverse obstetric outcomes may also affect a mother’s response to her infant, as demonstrated in the case of women undergoing Caesarean sections (57). In addition to these findings, the attachment-neurodevelopmental model provides us with a possible answer to the DOSMD challenge. If social adversity is common in developing societies (14, 24), “low social adversity” cannot answer the DOSMD challenge. Instead, it is possible that influences earlier in the life cycle, particularly childhood experiences, could buffer the adverse consequences of a potential or actual social defeat. A tentative proposal as to how this might happen runs as follows: Patients from the “developing” countries of the IPSS and DOSMD studies, such as India, often lived in extended families, an arrangement which presumably dated from their childhood. In such a set-up, abandonment of a child by either parent is relatively rare, due to strict social sanctions. Children in extended families often form attachment bonds
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to other caregivers, particularly grandparents, uncles and aunts, which may play an important role in the development of “theory of mind” skills. Moreover, in the event of an inevitable separation from one or the other parent, either temporary or permanent, such caregivers often fulfill the role of a primary attachment figure, with two positive consequences: 1) a mitigation of the effects of separation from the parent, and 2) a reduced risk of being exposed to severe forms of adversity, such as childhood abuse or gross neglect. If the above explanation is true, it also explains why more recent studies in these “developing” settings have not replicated the IPSS and DOSMD findings. Over time, social circumstances in many of these countries have changed. Urbanization and internal migration have led to extended families becoming rarer, and nuclear families more common. High rates of abuse and neglect have been reported in children faced with such changes (58).Under such circumstances, the protective mechanism postulated above may no longer hold good (24), and outcomes in these countries may approximate those seen in the IPSS and DOSMD’s “developed” countries over time (14). Biological plausibility of the ADC hypothesis Though the points listed above are suggestive, a far more important question is whether the structural and functional brain changes caused by disrupted childhood attachment parallel the well-established changes seen in the brains of patients with schizophrenia; if this is not the case, then the hypothesis would have to be discarded. However, there
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are a number of striking similarities between these two sets of changes, as enumerated below (Table 1) (Insert Table 1 Here) Though the above evidence is entirely consistent with the hypothesis, it must be interpreted with caution, as many of the cited studies are confounded by factors such as age at assessment, gender, type of childhood adversity and psychiatric comorbidity. Further research on the neurobiological changes caused by disrupted childhood attachment, with and without abuse, would place these associations on a firmer footing. Testing and refining the ADC hypothesis The role of attachment in schizophrenia can be tested both retrospectively and prospectively. In the former case, patients with a diagnosis of schizophrenia can be interviewed with structured instruments to assess both early (parental) and current measures of attachment, and their relationship to variables such as age at onset, disease course, treatment response, symptom profile, and outcome. If the hypothesis proposed above is correct, we would expect a strong correlation to be found between measures or markers of disrupted childhood attachment and psychosis, as well as a negative effect of such disruptions on the outcome of schizophrenia. Prospective studies could examine both the general population and “high-risk” groups, such as adolescents with prodromal symptoms or “psychosis risk syndrome”; if the hypothesis is correct, we would find a higher “conversion rate” to psychosis in high-risk subjects who have experienced childhood adversity.
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Second, further evidence must be obtained regarding the impact of disturbed childhood attachment on the symptomatology and outcome of schizophrenia. There is already some evidence that childhood trauma is associated with more severe positive symptoms and more frequent suicide attempts in schizophrenia (71). Moreover, Rosenberg et al (54) found a relationship between childhood adversity and a variety of adverse outcomes in schizophrenia, including comorbid substance use and imprisonment. These findings, though supportive of the hypothesis, need to be replicated. Third, the interaction between attachment and other risk factors for schizophrenia, such as vulnerability genes, substance abuse and infection, needs to be examined. There is already some evidence for gene-environment effects with regard to adversity in general (72), but a specific interaction between attachment and other factors still requires demonstration. Finally, the model can be refined by examining three important questions: 1. Is there any critical threshold of adversity or separation that is specifically “pathogenic”? 2. Are there any specific kinds of adversity, such as neglect or physical abuse, that can disrupt the key psychological processes implicated in schizophrenia, or is there a general “class effect” for all kinds of disrupted attachment? 3. What are the factors that may play a role in protecting against the harmful effects of disrupted or deviant attachment?
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Limitations of the hypothesis The model proposed above is consistent with the neurocognitive and neurodevelopmental models of schizophrenia, is supported by existing literature, and extends the efforts of some authors (such as Read’s “traumagenic model”) to examine the relationship between childhood adversity and psychosis. It also provides an empirically valid theoretical framework – attachment theory – in which this relationship can be examined. However, the following limitations must be borne in mind: 1. Disturbed attachment has been linked to a wide variety of disorders, both in childhood and adulthood. Moreover, disturbed attachment is far more common than schizophrenia in the general population. We cannot be certain if the relationship to schizophrenia is causal, or if disturbed attachment is a general vulnerability factor that raises susceptibility to a variety of mental disorders, including anxiety and depression. In all probability, certain forms of disturbed attachment – which have the particular effects of interfering with theory of mind skills and attribution styles – will be found to have a link to schizophrenia, as mentioned in the previous section. Delineating these attachment patterns is the key task that future researchers in this area will face. 2. The verification of this hypothesis, if successful, should not lead to a simplistic assignment of blame to a patient’s parents, and more specifically to his mother. Disturbed attachment is a complex phenomenon, and is often transmitted intergenerationally; the transmission of abusive parenting across generations has also been demonstrated in animal models. Parents who have difficulty bonding
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with their children have often received sub-optimal care from their own parents or caregivers, and their difficulties are compounded by the very real stress of caring for a child with schizophrenia. Such parents require support and empathy, rather than the blanket condemnation they were subjected to under the old psychodynamic models. 3. The plausibility of this hypothesis should not lead to simplistic reasoning about disturbed attachment being “the cause” of schizophrenia. Schizophrenia is best understood as a complex syndrome rather than as a unitary disorder, and the relative importance of various factors in a given patient may vary. At this point in time, we cannot be certain if attachment is relevant in all patients with schizophrenia, or only in a specific sub-set of them. Implications of the hypothesis The ramifications of an attachment-based hypothesis for schizophrenia are considerable, and can be considered at three levels: preventive, therapeutic and translational. From a preventive point of view, the most immediate application of this model would be to children and adolescents who are considered to be at a high risk of developing schizophrenia, either genetically or on the basis of their symptoms. Family intervention in such patients, aimed at strengthening attachment bonds and modifying interactional patterns, may effectively prevent them from developing the full syndrome of schizophrenia. This contention has some support from a literature review which
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demonstrated that family interventions have a more robust effect on the outcome of early psychosis than cognitive-behavioural therapy (73). It is too early to say if largerscale social programmes, aimed at assisting parents and enabling them to provide better care to their children, would actually reduce the incidence of schizophrenia; however, this corollary to the hypothesis cannot be ruled out. From a therapeutic point of view, this hypothesis points to the need for adequate psychosocial interventions in patients with schizophrenia, rather than a one-sided dependence on pharmacotherapy. While pharmacological interventions are invaluable in controlling acute symptoms, attachment-informed psychotherapies may assist patients in acquiring theory of mind skills and modifying attributions, thereby improving their social and occupational functioning, weakening paranoid delusions, and reducing the risk of relapses. From a translational perspective, the consequences of disturbed attachment, as seen in the delusions and other symptoms of schizophrenia, would provide valuable insights into the exact mechanisms by which childhood attachment leads to the development of interactional styles, attributions, and mentalization skills. Such mechanisms could be studied at various levels – behavioural, neurophysiological, genetic, and biochemical – and could enrich our knowledge not only of schizophrenia, but of human attachment and social cognition in general.
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Conclusion The ADC hypothesis outlined above is provisional, and is clearly in need of further support from clinical and community research. Besides, it cannot be viewed as a unitary “theory of schizophrenia”. Despite this, an attachment-informed perspective on schizophrenia, as outlined in this hypothesis, is consistent with both biological and psychosocial models of this disorder, strengthens them, and explains their interrelationships. This property sets it apart from other theories of schizophrenia and allows it to stand as a companion to them, thereby deepening our understanding of the developmental pathways that have schizophrenia as their end-point. Conflicts of interest: None
References:
1. McGrath JJ, Susser ES. New directions in the epidemiology of schizophrenia. MJA 2009; 190: S7-S9. 2. Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones T, Frackowiak RS. Patterns of cerebral blood flow in schizophrenia. Br J Psychiatry 1992; 160: 179-186. 3. Goghari VM, Sponheim SR, MacDonald AW. The functional neuroanatomy of symptom dimensions in schizophrenia: a qualitative and quantitative review of a persistent question. Neurosci Biobehav Rev 2010; 34: 468-486.
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4. Luhrmann TM. Social defeat and the culture of chronicity: or, why schizophrenia does so well over there and so badly here. Cult Med Psychiatry 2007; 31: 135172. 5. Harrington A. The fall of the schizophrenogenic mother. Lancet 2012; 379: 12921293. 6. Pantelis C, Yucel M, Wood SJ, McGorry PD, Velakoulis D. Early and late neurodevelopmental disturbances in schizophrenia and their functional consequences. Aust N Z J Psychiatry 2003; 37: 399-406. 7. Rapoport JL, Giedd JN, Gogtay N. Neurodevelopmental model of schizophrenia: update 2012. Mol Psychiatry 2012; 17: 1228-1238. 8. Sartorius N, Shapiro R, Jablensky A. The International Pilot Study of Schizophrenia. Schizophr Bull 1974; 11: 21-34. 9. Leff J, Sartorius N, Jablensky A, Korten A, Ernberg G. The International Pilot Study of Schizophrenia: five-year follow-up findings. Psychol Med 1992; 22: 131145. 10. Jablensky A, Sartorius N, Ernberg G et al. Schizophrenia: manifestations, incidence and course in different cultures. Psychol Med 1992; S20: 1-95. 11. Lin K-M, Kleinman A. Psychopathology and clinical course of schizophrenia: a cross-cultural perspective. Schizophr Bull 1988; 14: 555-567. 12. Edgerton RB, Cohen A. Culture and schizophrenia: the DOSMD challenge. Br J Psychiatry 1994; 164: 222-231. 13. Cohen A, Patel V, Thara R, Gureje O. Questioning an axiom: better prognosis for schizophrenia in the developing world? Schizophr Bull 2008; 34: 229-244.
21
14. Patel V, Cohen A, Thara R, Gureje O. Is the outcome of schizophrenia really better in developing countries? Rev Bras Psiquiatr 2006; 28: 149-152. 15. Bentall RP, Fernyhough C. Social predictors of psychotic experiences: specificity and psychological mechanisms. Schizophr Bull 2008; 34: 1012-1020. 16. Allardyce J, Boydell J. Review: the wider social environment and schizophrenia. Schizophr Bull 2006; 32: 592-598. 17. Veling W, Selten J-P, Susser E, Laan W, Mackenbach JP, Hoek HW. Discrimination and the incidence of psychotic disorders among ethnic minorities in the Netherlands. Int J Epidemiol 2007; 36: 761-768. 18. Cantor-Graae E, Selten J-P. Schizophrenia and migration: a meta-analysis and review. Am J Psychiatry 2005; 162: 12-24. 19. Selten J-P, Cantor-Graae E. Hypothesis: social defeat is a risk factor for schizophrenia? Br J Psychiatry 2007; 191 (S51): S9-S12. 20. Bebbington PE, Bhugra D, Brugha T et al. Psychosis, victimization and childhood disadvantage: evidence from the second British National Survey of Psychiatric Morbidity. Br J Psychiatry 2004; 185: 220-226. 21. Bendall S, Jackson HJ, Hulbert CA, McGorry PD. Childhood trauma and psychotic disorders: a systematic, critical review of the evidence. Schizophr Bull 2008; 34: 568-579. 22. Read J, Perry BD, Moskowitz A, Connolly J. The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model. Psychiatry 2001; 64: 319-345.
22
23. Morgan C, Kirkbride J, Leff J et al. Parental separation, loss and psychosis in different ethnic groups: a case-control study. Psychol Med 2007; 37: 495-503. 24. Burns J. Dispelling a myth: developing world poverty, inequality, violence and social fragmentation are not good for outcome in schizophrenia. Afr J Psychiatry 2009; 12: 200-205. 25. Bowlby J. Attachment and Loss. Volume 1: Attachment. London: Pimlico, Random House 1997. 26. Bowlby J. Attachment and Loss. Volume 2: Separation. London: Pimlico, Random House 1998. 27. Bowlby J. Attachment and Loss. Volume 3: Loss. London: Pimlico, Random House 1998. 28. Gallese V. The roots of empathy: the shared manifold hypothesis and the neural basis of intersubjectivity. Psychopathology 2003; 36: 171-180. 29. Meltzoff AN, Decety J. What imitation tells us about social cognition: a rapprochement between developmental psychology and cognitive neuroscience. Phil Trans R Soc Lond B 2003; 358: 491-500. 30. Fonagy P, Gergely G, Target M. The parent-infant dyad and the construction of the subjective self. J Child Psychol Psychiatry 2007; 48: 288-328. 31. Laible DJ, Thompson RA. Attachment and emotional understanding in preschool children. Dev Psychol 1998; 34: 1038-1045. 32. Ontai LL, Thompson RA. Patterns of attachment and maternal discourse effects on children’s emotion understanding from 3 to 5 years of age. Soc Development 2002; 11: 433-450.
23
33. Meins E, Fernyhough C, Russell J. Security of attachment as a predictor of symbolic and mentalising abilities: a longitudinal study. Soc Development 1998; 7: 1-24. 34. Schore AN. Attachment, affect regulation and the developing right brain: linking developmental neuroscience to pediatrics. Pediatrics Rev 2005; 26: 204-217. 35. Pruessner JC, Champagne F, Meaney MJ, Dagher A. Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using 11C-raclopride. J Neurosci 2004; 24: 2825-2831. 36. Chugani HT, Behen ME, Muzik O, Juhasz C, Nagy F, Chugani DC. Local brain functional activity following early deprivation: a study of postinstitutionalized Romanian orphans. Neuroimage 2001; 14: 1290-1301. 37. Garety PA, Kuipers E, Fowler D, Freeman D, Bebbington PE. A cognitive model of the positive symptoms of psychosis. Psychol Med 2001; 31: 189-195. 38. Garety PA, Bebbington P, Fowler D, Freeman D, Kuipers E. Implications for neurobiological research of cognitive models of psychosis: a theoretical paper. Psychol Med 2007; 37: 1377-1391. 39. Berry K, Barrowclough C, Wearden A. Attachment theory: a framework for understanding symptoms and interpersonal relationships in psychosis. Behav Res Therapy 2008; 46: 1275-1282. 40. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia : version III – the final common pathway. Schizophr Bull 2009; 35: 549-562.
24
41. Collip D, Myin-Germeyes I, van Os J. Does the concept of “sensitization” provide a plausible mechanism for the putative link between the environment and schizophrenia? Schizophr Bull 2008; 34: 220-225. 42. Varese F, Smeets F, Drukker M et al. Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr Bull 2012; 38: 661-671. 43. Brune M. “Theory of mind” in schizophrenia: a review of the literature. Schizophr Bull 2005; 31: 21-42. 44. Kohler CG, Walker JB, Martin EA, Healey KM, Moberg PJ. Facial emotion perception in schizophrenia: a meta-analytic review. Schizophr Bull 2010; 36: 1009-1019. 45. MacBeth A, Gumley A, Schwannauer M, Fisher R. Attachment states of mind, mentalization, and their correlates in a first-episode psychosis sample. Psychol Psychother 2011; 84: 42-57. 46. Butzlaff RL, Hooley JM. Expressed emotion and psychiatric relapse: a metaanalysis. Arch Gen Psychiatry 1998; 55: 547-552. 47. Rosenfarb IS, Nuechterlein KH, Goldstein MJ, Subotnik KL. Neurocognitive vulnerability, interpersonal criticism, and the emergence of unusual thinking by schizophrenic patients during family transactions. Arch Gen Psychiatry 2000; 57: 1174-1179. 48. Achim AM, Maziade M, Raymond E, Olivier D, Merette C, Roy M-A. How prevalent are anxiety disorders in schizophrenia? A meta-analysis and critical review on a significant association. Schizophr Bull 2011; 37: 811-821.
25
49. Moller H-J. Occurrence and treatment of depressive comorbidity/cosyndromality in schizophrenic psychoses: conceptual and treatment issues. World J Biol Psychiatry 2005; 6: 247-263. 50. Tops M, Van Peer JM, Korf J, Wijers AA, Tucker DM. Anxiety, cortisol and attachment predict plasma oxytocin. Psychophysiology 2007; 44: 444-449. 51. Wismer Fries AB, Ziegler TE, Kurian JR, Jacoris S, Pollak SD. Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. PNAS 2005; 102: 17237-17240. 52. Ross HE, Young LJ. Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior. Front Neuroendocrinol 2009; 30: 534-547. 53. Myhrman A, Rantakallio P, Isohanni M, Jones P, Partanen U. Unwantedness of pregnancy and schizophrenia in the child. Br J Psychiatry 1996; 169: 637-640. 54. Rosenberg SD, Lu W, Mueser KT, Jankowski MK, Cournos F. Correlates of adverse childhood events among adults with schizophrenia spectrum disorders. Psychiatr Serv 2007; 58: 245-253. 55. Mueser KT, Rosenberg SD, Goodman LA, Trumbetta SL. Trauma, PTSD and the course of severe mental illness: an interactive model. Schizophr Res 2002; 53: 123-143. 56. Cannon M, Jones PB, Murray RM. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry 2002; 159: 1080-1092. 57. Swain JE, Tasgin E, Mayes LC, Feldman R, Constable RT, Leckman JF. Maternal brain response to own baby-cry is affected by cesarean section delivery. J Child Psychol Psychiatry 2008; 49: 1042-1052.
26
58. Kacker L, Varadan S, Kumar P. Study on child abuse: India. New Delhi: Ministry of Women and Child Development, Government of India 2007. 59. De Bellis MD, Keshavan MS, Clark DB et al. Developmental traumatology part II: brain development. Biol Psychiatry 1999; 45: 1271-1284. 60. Carrion VG, Weems CF, Eliez S et al. Attenuation of frontal asymmetry in pediatric posttraumatic stress disorder. Biol Psychiatry 2001; 50: 943-951. 61. Keshavan MS, Tandon R, Boutros NN, Nasrallah HA. Schizophrenia, “just the facts”: what we know in 2008. Part 3: neurobiology. Schizophr Res 2008; 106: 89-107. 62. Belsky J, de Haan M. Annual research review: parenting and children's brain development: the end of the beginning. J Child Psychol Psychiatry 2011; 52: 409-428. 63. Dannlowski U, Stuhrmann A, Beutelmann V et al. Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biol Psychiatry 2012; 71: 286-293. 64. Choi J, Jeong B, Rohan ML, Polcari AM, Teicher MH. Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse. Biol Psychiatry 2009; 65: 227-234. 65. Kaufman J, Birmaher B, Perel J et al. Serotonergic functioning in depressed abused children: clinical and familial correlates. Biol Psychiatry 1998: 44: 973981. 66. Cowen PJ, Gadhvi H, Gosden B, Kolakowska T. Responses of prolactin and growth hormone to L-tryptophan infusion: effects in normal subjects and
27
schizophrenic patients receiving neuroleptics. Psychopharmacol 1985: 86: 164169. 67. Twardosz S, Lutzker JR. Child maltreatment and the developing brain: a review of neuroscience perspectives. Aggress Violent Behav 2010; 15; 59-68. 68. Watts-English T, Fortson BL, Gibler N, Hooper SR, De Bellis MD. The psychobiology of maltreatment in childhood. J Soc Issues 2006; 62: 717-736. 69. Zhang XY, Zhou DF, Cao LY, Wu GY, Shen YC. Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics. Neuropsychopharmacol 2005; 30: 1532-1538. 70. Eaton WW, Byrne M, Ewald H et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 2006; 163: 521-528. 71. Ucok A, Bikmaz S. The effects of childhood trauma in patients with first-episode schizophrenia. Acta Psychiatr Scand 2007; 116: 371-377. 72. Van Winkel R, Stefanis NC, Myin-Germeys I. Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction. Schizophr Bull 2008; 34: 1095-1105. 73. Bird V, Premkumar P, Kendall T, Whittington C, Mitchell J, Kuipers E. Early intervention services, cognitive-behavioural therapy and family intervention in early psychosis: systematic review. Br J Psychiatry 2010; 197: 350-356.
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“Childhood attachment and schizophrenia: the “attachment–developmentalcognitive” (ADC) hypothesis”
Financial support: No extramural funding was provided for this work. Conflicts of interest: None.
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Table 1: Neurobiological similarities between disrupted childhood attachment and schizophrenia
Domain
Changes observed
Remarks
Brain structure 1. Whole brain volume
2. Ventricular enlargement
3. Hippocampal volume
Reduced in maltreated Also seen in drug-naive children; earlier exposures patients with schizophrenia seem to have greater effects (61) (59, 60) Frequently reported in Some studies have found an patients with schizophrenia (61) association between ventricular enlargement and early childhood abuse (62)
Reduced both in children who have experienced trauma (62) and in healthy adults who have experienced childhood maltreatment (63) 4. White matter changes Reduced white matter tract integrity has been reported in adults exposed to verbal abuse during childhood (64)
Hippocampal volume, particularly gray matter volume, reduced in schizophrenia (61)
Similar changes have been reported in schizophrenia (61)
Neurotransmitter release 1. Dopamine transmission
Lower maternal care associated with increased dopamine release in response to stress (35)
2. Serotonin transmission
Increased prolactin response to 5-hydroxytryptophan seen
Potentially relevant for the formation of delusions (40)
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in depressed children with a Similar changes seen in history of neglect (65) drug-naive patients with schizophrenia (66)
Neuroendocrine changes Hypercortisolemia and overactivation of the hypothalamo-pituitaryadrenal (HPA) axis
Has been found as a Often found in patients with consequence of child neglect schizophrena; may reflect a and abuse in several studies stress response (61) (62, 67)
Others Immune dysregulation and pro-inflammatory activity
Elevated auto-antibody titres have been reported in abused girls by some researchers (68)
Recent evidence of immune and inflammatory dysfunction, including autoimmunity, in schizophrenia (69)
![[The glutamate hypothesis of schizophrenia].](/assets/img/hold.png)
