Cause Is Not Everything in Mental Illness - David Adam in Nature

In trying to make sense of psychological distress, research has moved away from psychological and sociological factors and is now focused almost exclusively on bio-medical factors. Yet we have no biological with which to diagnose or treat psychological distress.

Psychiatric research has yet to provide a single reliable biomarker to aid diagnosis and treatment. Self-reported symptoms and their subjective interpretations remain the basis for clinical diagnosis. Drug companies have walked away. The task of unravelling the biological pathways that drive mental illness, which are needed before drug targets can be identified, has been declared too difficult and too expensive.

This brief "editorial" is a response to the recent news that researchers have identified 108 genes associated with schizophrenia. Knowing the markers is important, but it's only partial.

The REAL question is what happens to trigger these genes (either turning them on or off). Several studies have found schizophrenia often has neglect in childhood (moreso than abuse, either emotional, physical, or sexual) as an etiological factor. How does neglect impact gene expression in the developing brain (epigenetics)? That, and others like it, is the real question.

Cause is not everything in mental illness

Welcome steps have been made in uncovering a biological basis for schizophrenia, but for many, the question of ‘why’ is unimportant, says David Adam.

30 July 2014

The past week has been big for mental illness. As reported last week in this journal, psychiatric researchers have uncovered a spread of genetic clues to schizophrenia, potentially shedding some biochemical light on how this dreadful disease develops. At the same time, a leading US centre for research on mental-health disorders announced a record US$650-million donation from philanthropist Ted Stanley to boost that work (see Nature 511, 393; 2014).

Good news all round. And more could yet follow: genetic understanding of psychiatric disorders, together with more research on the unusual ebb and flow of circuits in the brain, promise a revolution. Researchers of brain disorders compare the current state of their science to knowledge of cancer a decade or so ago, before molecular approaches could stratify patients and select specific treatments.

The latest study on schizophrenia could be a small step forward in this march. Or it could be another false start in a field that has endured more than its fair share. Psychiatric research has yet to provide a single reliable biomarker to aid diagnosis and treatment. Self-reported symptoms and their subjective interpretations remain the basis for clinical diagnosis. Drug companies have walked away. The task of unravelling the biological pathways that drive mental illness, which are needed before drug targets can be identified, has been declared too difficult and too expensive.

Of course, some perspective is needed. Psychiatric research had a long and painful birth. Just a generation or two ago, at a time when physicists had split the atom and biologists were deciphering the structure of DNA, a common treatment for schizophrenia and other mental disorders was a metal spike hammered up through the top of the eye socket and waggled around. With such a history, a lag of a mere decade or so behind cancer research can be taken as a sign of rapid progress.

Whether or not the latest study on the genetics of schizophrenia takes that progress forward, it has already contributed to the public debate around mental illness and public understanding of the issues. It has raised and highlighted the ‘C-word’: cause.

I have obsessive–compulsive disorder (OCD). That used to be a secret, but in April I published a book about the condition and my experiences of it. Despite its frequent portrayal as a behavioural quirk, OCD is a vicious and debilitating mental illness, with some similarities to the experiences of schizophrenia. Simply put, people with OCD can have some of the same dark ideas, thoughts and images as someone with schizophrenia, but the person with OCD is fully aware that they generate the thoughts themselves. (The psychosis that defines schizophrenia is characterized by a lack of such insight, and people with the condition typically attribute the intrusions to an external source.)

I now give talks about my OCD. A frequent question from the audience is one that I am still ill-prepared to answer: “What caused it?”

I don’t know, and more to the point I don’t care. For 20 years or so I have battled the symptoms. More recently, I sought and received treatment for those symptoms — a high daily dose of the antidepressant sertraline hydrochloride and several months’ worth of weekly sessions of cognitive behavioural therapy. It seemed to work, and without anyone — psychiatrists, psychologists or me — trying to identify the cause.

Perhaps the question from others is down to simple curiosity. I tell a human story and it is natural to want to know how such stories begin. Maybe there is a degree of self-interest because people do not want to follow the path that I did. It could be me who is unusual in not caring about a cause, but when I find out that people have cancer or heart disease or have had a stroke, the cause of their suffering is pretty far down my list of enquiries. In the past two or three years, I have met lots of other people with OCD and other mental disorders. Many of them, like me, do not know and do not seem to care about the who, the where, the why and the when of their illness. There is only how.

The other questions are not sinister. Instead, I think that they reflect an enduring mystery of mental illness. We do not know enough about the mind and the brain to build the backstory. (And as I said earlier, existing treatments do not require it.) Into this unknown creep the myths, the misunderstandings and the agendas. In psycho­analysis, for example, as devised by Sigmund Freud, cause is everything and, sure enough, psychoanalysts usually find a sub­conscious cause for a mental disorder that can be conveniently addressed by — oh, psychoanalysis.

The latest schizophrenia study helps to plug that causation gap. Schizophrenia has problems in the way that it is portrayed in the wider media, but the condition does escape the worst of the trivialization that plagues other forms of mental illness such as depression and OCD. No ignorant and patronizing opinion pieces have been penned in light of these latest developments to claim (as happens with depression, for instance) that the scientists are wrong and that schizophrenia is actually all about societal context and drug-company conspiracy. It is clearly an awful illness, and it — and by extension, other mental disorders — clearly has biological roots.

To expose those roots might lead to new treatments in future, or it might not. Either way, it helps.

Nature; 511,509 (31 July 2014). doi:10.1038/511509a

Related stories and links

• Gene-hunt gain for mental health 22 July 2014
• Biological insights from 108 schizophrenia-associated genetic loci 22 July 2014
• Schizophrenia: Genesis of a complex disease 22 July 2014
• Mental health: On the spectrum 24 April 2013
• Nature special: Schizophrenia

 

This article has been out for almost two months, but I just discovered it. Good timing, too, since I am currently writing an article refuting the new mandate from the National Institutes of Mental Health (NIMH) that dictates an essentially bio-genetic approach to understanding mental illness - and that will reject funding for projects that do not fit that agenda.

Certainly, there are some organic brain diseases, as discussed below (most of which are influenced in some way by the environment, through toxins, stress, injury, and other pathways). However, and this is the BIG however, the majority of the mental illness we encounter in the therapy room is sourced in relational dysfunction: abuse (sexual, physical, emotional, verbal), neglect (both physical and emotional), and other more subtle forms of relational trauma, that if consistent enough, result in anxiety, depression, poor self-image, and/or debilitating core beliefs about themselves and the world.

Until we admit these primary causes of mental illness into the research agenda, we are condemned to continue search for the mythical magic bullet medicine that will cure us of our pain.

Full Citation:
Schmitt, A, Malchow, B, Hasan, A, and Falkai, P. (2014, Feb 11). The impact of environmental factors in severe psychiatric disorders. Frontiers in Neuroscience: Systems Biology. doi: 10.3389/fnins.2014.00019

The impact of environmental factors in severe psychiatric disorders

Andrea Schmitt [1,2], Berend Malchow [1], Alkomiet Hasan [1], and Peter Falkai [1]

1. Department of Psychiatry and Psychotherapy, LMU Munich, Munich, Germany
2. Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo, São Paulo, Brazil

During the last decades, schizophrenia has been regarded as a developmental disorder. The neurodevelopmental hypothesis proposes schizophrenia to be related to genetic and environmental factors leading to abnormal brain development during the pre- or postnatal period. First disease symptoms appear in early adulthood during the synaptic pruning and myelination process. Meta-analyses of structural MRI studies revealing hippocampal volume deficits in first-episode patients and in the longitudinal disease course confirm this hypothesis. Apart from the influence of risk genes in severe psychiatric disorders, environmental factors may also impact brain development during the perinatal period. Several environmental factors such as antenatal maternal virus infections, obstetric complications entailing hypoxia as common factor or stress during neurodevelopment have been identified to play a role in schizophrenia and bipolar disorder, possibly contributing to smaller hippocampal volumes. In major depression, psychosocial stress during the perinatal period or in adulthood is an important trigger. In animal studies, chronic stress or repeated administration of glucocorticoids have been shown to induce degeneration of glucocorticoid-sensitive hippocampal neurons and may contribute to the pathophysiology of affective disorders. Epigenetic mechanisms altering the chromatin structure such as histone acetylation and DNA methylation may mediate effects of environmental factors to transcriptional regulation of specific genes and be a prominent factor in gene-environmental interaction. In animal models, gene-environmental interaction should be investigated more intensely to unravel pathophysiological mechanisms. These findings may lead to new therapeutic strategies influencing epigenetic targets in severe psychiatric disorders.

Introduction

Schizophrenia is a severe mental disorder starting at young adulthood (Kendler et al., 1996) with a prevalence of about 1% (Jablensky, 1995; McGrath et al., 2008). Each patient suffers from an individual combination of positive, negative, and affective symptoms as well as cognitive deficits, while the severity of these symptoms can change over time depending on the disease stage. Schizophrenia is characterized by prodromal phases with rather unspecific negative and cognitive symptoms, followed by the acute illness with prevailing positive symptoms (Falkai et al., 2011). Remission of psychosis is often incomplete with negative symptoms or even persisting positive symptoms being present in 30% of the sufferers (Hasan et al., 2012) and increasing to 60% in consideration of functionality (Gaebel et al., 2006). Positive symptoms consist of mainly acoustic hallucinations, delusions, disorganized speech, and disorganized behavior as well as thought disorder. The negative symptoms comprise blunted affect, avolition, anhedonia, asociality, and alogia (Crow, 1980; Andreasen et al., 1995). Apart from affective symptoms (e.g., anxiety, depressive mood, and suicidality), another domain refers to cognitive deficits with diminished episodic memory, executive function, and attention (Hoff et al., 1996, 2005; Heinrichs and Zakzanis, 1998; Albus et al., 2002, 2006), which represent a core feature of the disease and are main predictors for poor social-functioning outcome (Green, 1996).

Affective disorders, including major depressive disorder and bipolar disorder with manic episodes, belong to the most prevalent psychiatric diseases. Being among the severe psychiatric diseases (Alsuwaidan et al., 2009), Major depressive disorder has a lifetime prevalence between 16 and 20% (Williams et al., 2007) while lifetime prevalence of bipolar disorder is around 3% in the general population (Merikangas et al., 2007). According to DSM-IV (American Psychiatric Association, 1994) symptoms include loss of energy, social withdrawal, and melancholia in depressive episodes of both major depression and bipolar disorder, and elation, irritability, increased energy with hyperactivity, racing thoughts, pressured rapid speech, decreased need for sleep and an increased involvement of pleasured activities in manic episodes of bipolar disorder. In bipolar disorder, instability of mood is one of the core symptoms, whereas melancholia is the most common sign of depressive episodes (Meyer and Hautzinger, 2003). Furthermore, apart from affective symptoms, both types of affective disorders display impaired cognitive performance, mainly in attention, memory, and executive tasks (Torres et al., 2007). However, because of the individuality of patient's symptoms, current psychiatric diagnostic manuals are not always valid and major psychiatric disorders like schizophrenia, bipolar disorder, and depression are considered as a continuum with different severity of cognitive deficits as common trait (Hill et al., 2013).

In schizophrenia, twin studies show a heritability of about 60–80% (Sullivan et al., 2003), whereas in bipolar disorder and major depression heritability has been estimated to be 6–80 and 32%, respectively (Wray and Gottesman, 2012). Genome-wide association studies (GWAS) revealed a multitude of genetic risk variants (single nucleotide polymorphisms, SNP) with low effect (Schwab and Wildenauer, 2013). New risk SNPs with high significance are located in genes for Zinc finger protein (ZNF804a), transcription factor 4 (TCF4), micro-RNA 137 (Mir137), the L-type voltage-gated calcium channel (CACNA1C), and CACNB2, Inter-alpha globulin inhibitor H3 and H5 (ITIH3-ITIH4) as well as ankyrin3 (Ank3) with mostly unknown neurobiological consequences (Schwab and Wildenauer, 2013). Ank3 and CACNA1C are also relevant for bipolar disorder (Ferreira et al., 2008) and CACNB2 has been found to be associated with schizophrenia, bipolar disorder and major depression (Cross-Disorder Group of the Psychiatric Genomics Consortium et al., 2013). In a new GWAS study, Ripke et al. (2013) estimated that in schizophrenia about 8.300 SNPs contribute to a common risk of 32%, suggesting that environmental factors interacting with the genetic background contribute to the pathophysiology (Manolio et al., 2009). In schizophrenia, environmental factors are proposed to play a role up to 60% (Benros et al., 2011) (Figure 1).

FIGURE 1

Figure 1. Interacting risk genes and environmental factors contribute to increase the risk of schizophrenia. The figure shows the estimated heritability risk to develop schizophrenia as a factor of grade of next of kin. The right side illustrates the contribution of different environmental factors such as infections, obstetric complications, stress periods, and cannabis abuse.

Neurodevelopment and Psychiatric Disorders

During the last decades, schizophrenia has been regarded as a neurodevelopmental disorder. Defective genes and environmental factors may interact to induce symptoms of the disease. The so-called “neurodevelopmental hypothesis” proposes schizophrenia to be related to adverse conditions leading to abnormal brain development during the perinatal period, whereas symptoms of the disease appear in early adulthood after the synaptic pruning process (Weinberger, 1996). In the “two-hit” model, early perinatal insults (genetic background and/or environmental factors) may lead to dysfunction of neuronal circuits and vulnerability to the disease, while a second “hit” during a critical brain development period in adolescence may induce the onset of the disease (Keshavan and Hogarty, 1999). The early perinatal period has been shown to be critical for proper brain development and more specifically the late first and second trimester have been implicated in the pathophysiology of the disease (Fatemi and Folsom, 2009). During adolescence, a synaptic pruning process with excessive elimination of synapses and loss of synaptic plasticity may lead to exacerbation of symptoms in the predisposed brain (Keshavan and Hogarty, 1999; Schmitt et al., 2011a). Additionally, myelination of the heteromodal association cortex like the prefrontal cortex occur during this period (Peters et al., 2012) and decreased fractional anisotropy which corresponds to deficits in myelination has consistently been reported in schizophrenia, suggesting disturbances in fronto-limbic connections (Yao et al., 2013). The prefrontal cortex is highly connected with the hippocampus and this neuronal network has been shown to be disturbed in schizophrenia, mainly due to neurodevelopmental disturbances (Bullmore et al., 1997; Peters et al., 2012; Rapoport et al., 2012). Accordingly, in animal models, perinatal hippocampal lesions induced dysfunction of the prefrontal cortex in adulthood (Lipska, 2004). The disconnection of the hippocampus during brain development alters prefrontal cortical circuitry, function and neurocognition such as prepulse inhibition of acoustic startle response and represents a potent neurodevelopmental animal model for schizophrenia.

Meta-analyses of structural magnetic resonance imaging studies revealed decreased hippocampal volumes and increased ventricles in first-episode schizophrenia patients, confirming the presence of neuropathology before diagnosis is possible (Steen et al., 2006; Vita et al., 2006; Adriano et al., 2012). Even in patients with ultrahigh risk to develop schizophrenia, diminished gray matter of prefrontal and hippocampal regions has been detected compared to healthy controls and in patients experiencing later transition to schizophrenia these volume deficits were yet more pronounced (Witthaus et al., 2009, 2010; Wood et al., 2010). In a comparative analysis, both schizophrenia patients and patients with treatment-resistant major depressive disorder exhibited reduced hippocampal volumes (Maller et al., 2012). Reduced hippocampal volume has also been confirmed in patients with recurrent and chronic depression (Cole et al., 2011). Shape analysis revealed deformations in subfields in the tail of the right hippocampus as well as bilateral volume reductions in patients with first-episode depression (Cole et al., 2010; Meisenzahl et al., 2010), while during the course of the disease further reductions have only been detected in schizophrenia. The presence of alterations in first-episode depression is consistent with a neurodevelopmental hypothesis of early stress experience, especially since the hippocampus plays a major role in inhibiting stress response (McEwen and Magarinos, 2001), providing inhibitory feedback to the hypothalamic-pituitary-adrenal (HPA) axis (Fanselow, 2000).

Stress During Neurodevelopment

Potential stress-inducing factors are migration and urbanicity, which both have been related to schizophrenia. Meta-analyses show an association with urban environment after controlling for minority status (van Os et al., 2010). Individuals living in a higher degree of urbanization had a higher risk to develop schizophrenia than people living in rural areas with a dose-dependent relationship (Pedersen and Mortensen, 2001). In healthy controls, city living was associated with increased amygdala activity, whereas urban upbringing affected the anterior cingulate cortex, affective, and stress response (Lederbogen et al., 2011). In first- and second-generation migrants as well as in minority groups across all cultures, psychotic symptoms have been shown to be increased (Rapoport et al., 2012). According to the “social defeat hypothesis” it has been assumed that social status and degree, e.g., occupying a minority position or experiencing social exclusion, promotes the development of schizophrenia (van Os et al., 2010).

Maltreated children suffer more likely from severe psychiatric disorders such as major depression, bipolar disorder, post-traumatic stress disorder, anxiety disorders, substance abuse and schizophrenia. Childhood maltreatment has been associated with reduced hippocampal volume and amygdala hyperreactivity and also predicts poor treatment outcome (Teicher and Samson, 2013). To date, apart from a genetic vulnerability, stress is widely accepted as risk factor for depression. The stress sensitization hypothesis describes that the first episode of depression sensitizes an individual to stress for which reason subsequent episodes require less stress to be triggered (Shapero et al., 2014). In extension of this hypothesis, early adverse childhood experiences including emotional abuse, physical, and sexual abuse or neglect have been shown to predict depressive symptoms in adulthood (Shapero et al., 2014). Indicating a gene-environment interaction, genetic factors such as polymorphisms in the serotonin transporter or methylenetetrahydrofolate reductase have been reported to interact with developmental stress to increase the risk for depression (Karg et al., 2011; Lok et al., 2013). However, individual genetic background influences the incidence of depression in response to stress and only a part of the persons experiencing stressors develops depression (Keers and Uher, 2012). Moreover, childhood abuse is known to induce psychotic symptoms and suicidal behavior in patients with major depression and bipolar disorder (Arseneault et al., 2011; Tunnard et al., 2014). Early psychotic symptoms represent a risk for developing schizophrenia. In a meta-analysis of 18 case-control studies, Varese et al. (2012) filtered adverse experiences in childhood to significantly increase the risk to develop psychosis and schizophrenia. The neurobiological consequence of stress sensitization involves dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis, contributing to dopamine sensitization in mesolimbic areas and increased stress-induced striatal dopamine release (van Winkel et al., 2008).

The major stress system of the body is the HPA axis, a neuroendocrine system involved in the production of the stress hormone cortisol by adrenal glands. In a subset of patients with major depression, but also in patients with severe psychiatric disorder across phenotypic diagnosis, a dysfunction of the HPA axis has been detected (MacKenzie et al., 2007; Kapur et al., 2012). Depressed patients with a history of childhood abuse have enhanced HPA axis response to psychosocial stress and attenuated cortisol response to application of the synthetic corticosteroid dexamethasone (Heim et al., 2000). In animal models, acute or chronic stress decreased BDNF levels in the hippocampus inclusive the dentate gyrus (Neto et al., 2011). Along with this hypothesis, stress is known to reduce hippocampal dendrites (Magarinos et al., 2011). It additionally increases plasma and adrenal corticosterone levels and application of this hormone reduced hippocampal BDNF levels, mimicking stress reaction (Neto et al., 2011). Chronic stress or repeated administration of glucocorticoids results in degeneration of hippocampal neurons with decreased soma size and atrophy of dendrites (Sapolsky et al., 1990; Watanabe et al., 1992). Thus, volume loss in vulnerable brain regions like the hippocampus as reported for affective disorders may indeed be mediated by stress-induced glucocorticoid neurotoxicity (Arango et al., 2001; Frodl and O'Keane, 2013). In an animal model of depression, the learned helplessness paradigm, inescapable stress induces downregulation of stem cell proliferation (neurogenesis) in the dentate gyrus of the hippocampus (Malberg and Duman, 2003). Stress is additionally known to influence synaptic plasticity in the prefrontal cortex (Rajkowska, 2000). Mediating gene-environmental interactions, epigenetic mechanisms altering chromatin structure such as histone acetylation and DNA methylation may link effects of environmental factors such as stress to transcriptional regulation of specific genes. Depression-like behavior and antidepressant action have been found to be regulated by epigenetic mechanisms (Sun et al., 2013). For example, stress is known to increase histone methylation at the corresponding promoters of the BDNF gene.

Maternal stress during the prenatal period has been related to schizophrenia, depression, and anxiety (Markham and Koenig, 2011), which also applies to autism spectrum disorder and attention deficit hyperactivity disorder (Class et al., 2014). It includes maternal psychological stress exposure e.g., due to bereavement, unwantedness of a pregnancy, natural disaster or war experience (Brown, 2002; Spauwen et al., 2004; Sullivan, 2005; Meli et al., 2012). Children of mothers who experienced e.g., death of relatives or other serious life events developed schizophrenia to a higher degree (Khashan et al., 2008). War experience e.g., during world war II or Israel's Six-Day-War has also been regarded as a critical factor (van Os and Selten, 1998; Malaspina et al., 2008). Especially during the first or second trimester of pregnancy, a vulnerable brain development period may exist for those stress factors. Beside schizophrenia, depression, and anxiety are consequences of exposure to gestational stress (Torrey et al., 1996; Watson et al., 1999; Brown et al., 2000). Prenatal stress is known to influence function of the HPA axis and secretion of glucocorticoid hormones as well protective capacity of the placenta (Owen et al., 2005; Weinstock, 2005, 2008). In addition to effects on stress hormones, prenatal stress influences the fetal transcriptome through microRNA (miRNA) regulation as an epigenetic mechanism, which links environmental factors to altered gene expression in the pathophysiology of schizophrenia and bipolar disorder (Zucchi et al., 2013). Among 435 miRNAs, 19% exhibited reduced expression in the prefrontal cortex in schizophrenia, or more pronounced in bipolar disorder (Moreau et al., 2011). While 18 miRNAs have been found to be differentially expressed, the miRNA miR-497 and miR-29c have been validated to be overexpressed in exosomes of the prefrontal cortex of patients with schizophrenia or bipolar disorder (Banigan et al., 2013). Moreover, methylation or hydroxymethylation of specific genes or promotors regulates gene expression (Akbarian, 2010). Hypermethylation of sex-determining region Y-box 10 (SOX10) has been reported in schizophrenia, whereas in bipolar disorder hypomethylation of HLA complex group 9 (HCG9), ST6 (alpha-N-acetyl-neuranminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase (ST6GALNAC), and hypermethylation of the serotonin transporter SLCA4 and proline rich membrane anchor 1 (PRIMA1) has been observed (Kato and Iwamoto, 2014). In the frontal cortex of schizophrenia patients, genome-wide methylation analysis revealed differential methylation of 817 genes in promotor regions, among them genes which previously have been associated with schizophrenia (Wockner et al., 2014). Histone modification of chromatin is another epigenetic mechanism to influence gene expression (Peter and Akbarian, 2011). In schizophrenia, altered histone methyltransferases have been detected in the parietal cortex and represent potential future targets for novel treatment strategies (Chase et al., 2013). After prenatal stress in mice, abnormalities in DNA methylation have been described in GABAergic neurons and been related to a schizophrenia-like behavioral phenotype (Matrisciano et al., 2013).

Altered expressions of glucocorticoid receptors and corticotropin-releasing hormone (CRH) in the hippocampus and amygdala have been reported to result from prenatal stress and may be related to increased anxiety and depression-related behavior (Markham and Koenig, 2011). Cognitive deficits of working memory, spatial memory and novel object recognition, related to dysfunctions of the hippocampus and prefrontal cortex, have repeatedly been associated with prenatal stress in animal models and implicate its relationship to severe psychiatric disorders (Markham and Koenig, 2011). Other behavioral consequences are increased locomotor activity and deficits in prepulse inhibition of acoustic startle response (PPI) (Koenig et al., 2005). Increased subcortical and decreased prefrontal dopamine activity after prenatal stress interestingly corresponds to neurotransmitter hypotheses of schizophrenia (Carboni et al., 2010). As a correlate of negative symptoms, social interaction has been reported to be decreased in animals with experience of prenatal stress (Lee et al., 2007). Investigating gene-environmental interaction, a social deficit has been revealed in SNAP-25 knockout mice, which represents a synaptic protein involved in neurotransmitter release, combined with prenatal stress paradigm (Oliver and Davies, 2009).

Some retrospective studies investigated consequences of prenatal food starvation during the “Dutch hunger winter 1944–1945” (Susser et al., 1996; Hoek et al., 1998) and Chinese famine during 1959–1961 (St Clair et al., 2005; Xu et al., 2009). In these investigations, famine episodes of mothers were related to increased risk for schizophrenia in the offspring. Exposure to famine has also been associated with mood disorders and antisocial behavior (Lumey et al., 2011) However, these data are based on ecological inquiries and other factors such as prenatal stress, inflammation, obstetric complications, and toxic substances are not controlled for. Despite these limitations, animal studies revealed effects for protein restriction, choline and vitamin D deficiency on dopamine-related behavior such as locomotor activity and sensorimotor gating, cognition and anxiety, or depression-related behaviors (Markham and Koenig, 2011).

Birth and Obstetric Complications

Several meta-analyses have shown an association between complications of pregnancy and delivery and schizophrenia. This applies to obstetric complications of preeclampsia, bleeding, rhesus incompatibility and diabetes, asphyxia, uterine atony, emergency Ceasarian section, and fetal abnormalities such as low birth weight, congenital malformations, and small head circumference. Effect sizes have been estimated between two and three with the highest effect showing emergency Caesarian section, placental abruption, and low birth weight (Cannon et al., 2002a). Schizophrenia has been associated with boys which were small for gestational age at birth (odds ratio 3.2) (Hultman et al., 1999). Children who experienced fetal hypoxia and later developed schizophrenia or affective disorders had basically lower birth weights, indicating that birth weight is a general marker of viability of the intrauterine environment (Fineberg et al., 2013). An odds ratio of 2.0 has been detected by a meta-analysis of Geddes and Lawrie (1995). The same group investigated another meta-analysis of different obstetric complications and found associations between schizophrenia and use of incubator, prematurity and premature rupture of membranes, while low birthweight and use of forceps during delivery were less consistently related to the disorder (Geddes et al., 1999). Maternal bleeding during pregnancy has been found to be associated with schizophrenia with an odds ratio of 3.5 (Hultman et al., 1999). Interestingly, in individuals at high risk for psychosis, those who de facto converted into psychosis had more obstetric complications than non-converting individuals (Mittal et al., 2009). A common factor of all these complications is perinatal hypoxia (Zornberg et al., 2000), which in rats induced a deficit in prepulse inhibition of acoustic startle response (PPI) in adulthood. This behavioral correlate to schizophrenia responded to treatment with the atypical antipsychotic clozapine (Schmitt et al., 2007; Fendt et al., 2008).

The PPI paradigm reflects function of a specific network of brain regions, among them the hippocampus, prefrontal cortex, striatum, and nucleus accumbens (Swerdlow et al., 2001). Especially the hippocampus and basal ganglia are vulnerable to hypoxia-ischemia in the neonate (Morales et al., 2011). Bilateral hippocampal atrophy has been detected in adolescents with a history of perinatal asphyxia diagnosed as hypoxic-ischemic encephalopathy, along with worse verbal long-term memory (Maneru et al., 2003). In schizophrenia, patients with obstetric complications have shown reduced hippocampal volumes (McNeil et al., 2000; Van Erp et al., 2002; Schulze et al., 2003; Ebner et al., 2008), while no effects have been observed in volumes of basal ganglia (Haukvik et al., 2010). However, effects of antipsychotic medication have to be taken into consideration when investigating brain regions (Lieberman et al., 2005). In patients, fetal hypoxia has been related to increased ventricular size and reduced cortical gray matter (McNeil et al., 2000; Cannon et al., 2002b; Falkai et al., 2003), but results are not consistent (Haukvik et al., 2009). Assessment of the two-dimensional gyrification index (GI) revealed no relationship between obstetric complications and cortical folding (Falkai et al., 2007), but after application of a three-dimensional local GI calculation cortical gyrification has been observed to be reduced in the Broca's area in patients and healthy controls with obstetric complication (Haukvik et al., 2012). Since early stages of gyrification take place during gestational week 16 with a rapid increase in the third trimester (Armstrong et al., 1995), this possibly reflects neurodevelopmental disturbances.

In a meta-analysis of 22 studies, the pooled odds ratio for exposure to obstetric complications and subsequent development of bipolar disorder was 1.01 and for development of major depression 0.61, not supporting the association with affective disorder (Scott et al., 2006). However, in a national register study of 1.3 million Swedes, preterm birth has been significantly associated with affective disorders: those with less than 32 weeks gestation had a 2.9-fold higher risk to develop major depression and 7.4% more likely to have bipolar disorder (Nosarti et al., 2012). In a structural MRI study of 79 patients with bipolar disorder and 140 healthy controls from a Norwegion registry, perinatal asphyxia including a hypoxic state lead to smaller amygdala volumes in the bipolar group with perinatal asphyxia, while the non-psychotic group had an association with smaller hippocampal volumes (Haukvik et al., 2013). This is important for the pathophysiology of bipolar disorder, since meta-analyses have revealed smaller amygdala and hippocampus volumes in lithium-naïve patients with bipolar disorder (Hallahan et al., 2011; Hajek et al., 2012).

The consequences of fetal hypoxia comprise neuronal death, white matter damage with impaired myelination and reduced growth of dendrites with more profound effects at mid than late gestation (Rees et al., 2008). Apart from axonal degeneration, especially oligodendrocytes and periventricular white matter are sensible for the influence of oxygen restriction (Kaur et al., 2006). Additionally, an excess of glutamate via hypofunction of the N-methyl-D-aspartate (NMDA) receptor, which has been proposed to play a major role in the pathophysiology of schizophrenia (Hashimoto et al., 2013; Weickert et al., 2013), may damage oligodendroglia and myelin and influence oligodendrocyte differentiation (Mitterauer and Kofler-Westergren, 2011; Cavaliere et al., 2013). Thereby, contributing to cognitive deficits, increased glutamate levels may induce a synaptic imbalance between axons and oligodendroglia, affecting the glial network (syncytium) which is composed of oligodendrocytes and astrocytes (Mitterauer, 2011). In schizophrenia, decreased oligodendrocyte number has been detected in CA4 of the hippocampus and prefrontal cortex (Hof et al., 2003; Schmitt et al., 2009). Although no astrocytosis has been found in schizophrenia (Schmitt et al., 2009), dysfunction of astrocytes may be present in psychiatric disorders (Mitterauer, 2011). At the paranodal junctions between axons and terminal loops of oligodendrocytes, contactin-associated protein is expressed and has been reported to be downregulated in schizophrenia, thus modulating glia-neuronal interaction (Schmitt et al., 2012). In addition to these glial networks, microglia is known to be activated by hypoxic periods and may mediate cell damage via production of nitric oxide synthase, linking neonatal hypoxia to inflammatory processes (Kaur et al., 2006). In the rat model of perinatal hypoxia, cDNA microarray derived analysis revealed synaptic genes like complexin 1, syntaxin 1A, SNAP 25, neuropeptide Y, and neurexin 1 to be deregulated in several cortical regions and striatum during adulthood. In this study, clozapine treatment had effects on gene expression (Sommer et al., 2010). These findings are relevant to schizophrenia, which has been described as a disease of dysconnectivity on the synaptic and systematic level (Schmitt et al., 2011a, 2012).

Inflammation During Pregnancy

As to offspring of mothers exposed to influenza, several epidemiological studies have demonstrated an increased risk for schizophrenia. However, infections with other viruses such as measles, rubella, varicella-zoster, polio, and herpes as well as bacteria and parasites (Toxoplasma gondii) also confer an increased risk of schizophrenia (Hagberg et al., 2012). Moreover, maternal infections and subsequent inflammatory processes and brain injury during pregnancy are known to be associated with preterm labor, especially at <30 weeks of gestation (Dammann et al., 2002; Goldenberg et al., 2008). These complications are known to affect white matter structures such as corpus callosum or other major white matter tracts and may be associated with neurodevelopmental injury of oligodendrocytes in schizophrenia (Chew et al., 2013). In fact, decreased numbers of oligodendrocytes have been detected in the hippocampus and prefrontal cortex in post-mortem brains of schizophrenia patients and may affect subsequent myelination (Hof et al., 2002; Schmitt et al., 2009). Pro-inflammatory cytokine release has been described as common mechanism of infectious processes (Brown, 2012; Garbett et al., 2012). In the prefrontal cortex of schizophrenia patients, gene expression analysis revealed increased expression of inflammatory genes along with activation of microglia (Beumer et al., 2012; Fillman et al., 2013), but results in the superior temporal cortex also point to the reduced expression of immune-related genes (Schmitt et al., 2011b). In which manner these post-mortem findings are related to perinatal insults is not yet resolved. In animal studies, maternal infection induced behavioral abnormalities in early adulthood comparable to schizophrenia such as deficits in PPI, social interaction and working memory (Meyer and Feldon, 2009).

Challenging Future Investigations: Gene-Environmental Interaction

Many efforts have been made to unravel the genetic background of severe psychiatric disorders. Recent GWAS point toward a partial overlap in susceptibility between schizophrenia and affective disorders (Cross-Disorder Group of the Psychiatric Genomics Consortium et al., 2013). For example, the risk variant of the alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene is associated with schizophrenia, bipolar disorder and major depression (Green et al., 2010). This genotype has been shown to influence hippocampal activation during episodic memory encoding and retrieval (Krug et al., 2013). However, effect sizes for common genetic variants so far were small (Brown, 2011; Réthelyi et al., 2013). Environmental factors, especially those affecting molecular and structural processes in relevant brain regions during neurodevelopment, are supposed to interact with genetic factors to induce severe psychiatric disorders (Harrison and Weinberger, 2005). For example, a large number of schizophrenia candidate genes are known to be regulated by hypoxia (Fatemi and Folsom, 2009; Schmidt-Kastner et al., 2012). In transgenic animal models of schizophrenia, stressful events have been induced to reinforce the behavioral phenotype (Haque et al., 2012; Hida et al., 2013). Future animal studies should combine risk variants of susceptibility genes with several environmental factors such as perinatal infection, stress and hypoxia to develop valid models of severe psychiatric disorders. These models could be useful to understand pathophysiological brain mechanisms and to develop new treatment strategies aiming at risk-based therapy and prevention of symptoms of severe psychiatric disorders.

Conflict of Interest Statement

Berend Malchow declares no conflicts of interest. Alkomiet Hasan has been invited to scientific conferences by Janssen Cilag, Pfizer, and Lundbeck. He received paid speakership by Desitin and is member of the Roche advisory board. Andrea Schmitt was honorary speaker for TAD Pharma and Roche and has been member of the Roche advisory board. Peter Falkai until 12/2011 has been member of the advisory boards of Janssen-Cilag, BMS, Lundback, Pfizer, Lilly, and AstraZeneca and received an educational grant from AstraZeneca and honoraria as lecturer from Janssen-Cilag, BMS, Lundbeck, Pfizer, Lilly, and AstraZeneca.

References are available at the Frontiers site.

The PDM - An Alternative to the DSM

The PDM is the the Psychodynamic Diagnostic Manual (2006, $21.93 at Amazon), a collaborative effort of the American Psychoanalytic Association, International Psychoanalytical Association, Division of Psychoanalysis (39) of the American Psychological Association, American Academy of Psychoanalysis and Dynamic Psychiatry, and the National Membership Committee on Psychoanalysis in Clinical Social Work.

I am including the introduction (below), but also check out the Table of Contents. The Task Force that created the Manual is a who's who of mainstream psychoanalytic therapists, but there are no real representatives of the intersubjective systems, relational, or Self Psychology branches of psychoanalysis, which is where the real innovation is occurring.

While this volume is a step in the direction I recently advocated for, it still comes up quite short of being intersubjective, relational, and attachment-based in its conception of mental distress.

Introduction to the PDM

The Psychodynamic Diagnostic Manual (PDM) is a diagnostic framework that attempts to characterize the whole person--the depth as well as the surface of emotional, cognitive, and social functioning. It emphasizes individual variations as well as commonalities. We hope that this framework will bring about improvements in the diagnosis and treatment of mental disorders and will permit a fuller understanding of the functioning of the mind and brain and their development. The goal of the PDM is to complement the DSM and ICD efforts of the past 30 years in cataloguing symptoms by explicating the full range of mental functioning.

The PDM is based on current neuroscience, treatment outcome research, and other empirical investigations. Research on brain development and the maturation of mental processes suggests that patterns of emotional, social, and behavioral functioning involve many areas working together rather than in isolation.

Outcome studies point to the importance of dealing with the full complexity of emotional and social patterns. Numerous researchers (e.g., Blatt, this volume; Norcross 2002; Wampold 2001) have concluded that the nature of the psychotherapeutic relationship, reflecting interconnected aspects of mind and brain operating together in an interpersonal context, predicts outcome more robustly than any specific treatment approach per se . Westen, Novotny, and Thompson-Brenner (2004 and this volume) have presented evidence that treatments that focus on isolated symptoms or behaviors (rather than personality, emotional, and interpersonal patterns ) are not effective in sustaining even narrowly defined changes. Shedler and Westen, Dahlbender and colleagues, Blatt, and others (this volume) have developed reliable ways to measure complex patterns of personality, emotion, and interpersonal processes that constitute the active ingredients of the psychotherapeutic relationship. A number of recent reviews (e.g., Fonagy's and Leichsenring's in this volume) demonstrate that in addition to alleviating symptoms, psychodynamically based therapeutic approaches improve overall emotional and social functioning.

The PDM was created though a collaborative effort of the major organizations representing psychoanalytically oriented mental health professionals; namely, the American Psychoanalytic Association, the International Psychoanalytical Association, the Division of Psychoanalysis (39) of the American Psychological Association, the American Academy of Psychoanalysis, and the National Membership Committee on Psychoanalysis in Clinical Social Work. Their presidents formed a steering committee and recommended members to serve on work groups to construct this classification system.

The diagnostic framework formulated by the PDM work groups systematically describes:

• Healthy and disordered personality functioning ;
• Individual profiles of mental functioning, including patterns of relating, comprehending and expressing feelings, coping with stress and anxiety, observing one's own emotions and behaviors , and forming moral judgments ;
• Symptom patterns, including differences in each individual's personal, subjective experience of symptoms.

The Psychodynamic Diagnostic Manual adds a needed perspective to existing diagnostic systems. In addition to considering symptom patterns described in existing taxonomies, it enables clinicians to describe and categorize personality patterns, related social and emotional capacities, unique mental profiles, and personal experiences of symptoms. It provides a framework for improving comprehensive treatment approaches and understanding both the biological and psychological origins of mental health and illness.

Rationale for the PDM

A clinically useful classification of mental health disorders must begin with an understanding of healthy mental processes. Mental health comprises more than simply the absence of symptoms. It involves a person's overall mental functioning, including relationships; emotional depth, range, and regulation; coping capacities; and self-observing abilities. Just as healthy cardiac functioning cannot be defined simply as an absence of chest pain, healthy mental functioning is more than the absence of observable symptoms of psycho pathology. It involves the full range of human cognitive, emotional, and behavioral capacities.

Any attempt to describe and classify deficiencies in mental health must therefore take into account limitations or deficits in many different mental capacities, including ones that are not necessarily overt sources of pain. For example, as frightening as anxiety attacks can be, an inability to perceive and respond accurately to the emotional cues of others-a far more subtle and diffuse problem-may constitute a more fundamental difficulty than periodic episodes of unexplained panic. A deficit in reading emotional cues may pervasively compromise relationships and thinking and may itself be a source of anxiety.

That a comprehensive conceptualization of health is the foundation for describing disorder may seem self-evident, and yet the mental health field has not developed its diagnostic procedures accordingly. In the last two decades, there has been an increasing tendency to define mental problems primarily on the basis of observable symptoms, behaviors, and traits, with overall personality functioning and levels of adaptation noted only secondarily. There is increasing evidence, however, that both mental health and psychopathology involve many subtle features of human functioning, including affect tolerance, regulation, and expression; coping strategies and defenses; capacities for understanding self and others; and quality of relationships. Mounting evidence from neuroscience and developmental studies supports the position that mental functioning, whether optimal or compromised, is highly complex. To ignore mental complexity is to ignore the very phenomena of concern. After all, our mental complexity defines our most human qualities.

Over the past 30 years or so, in the hope of developing an adequate empirical basis for diagnosis and treatment, the mental health field has progressively narrowed its perspective, focusing more and more on isolated symptoms. The whole person has been less visible than the various disorder constructs on which researchers can find agreement. Recent reviews of this effort have raised the possibility that such a strategy was misguided. Ironically, emerging evidence suggests that oversimplifying mental health phenomena in the service of attaining consistency of description (reliability) and capacity to evaluate treatment empirically (validity) may have compromised the laudable goal of a more scientifically sound understanding of mental health and psychopathology. Most problematically, reliability and validity data for many disorders are not as strong as the mental health community had hoped they would be. Allen Frances, Chair of the DSM-IV American Psychiatric Association Task Force , recently acknowledged (Spiegel 2005) that the desired reliability has not been obtained.

In a recent commentary in the Journal of the American Medical Association , Paul McHugh (2005) pointed out that medicine has moved beyond simply describing symptoms to categorizing disorders according to the nature of the functional impairment and etiological factors (if known). Contending that the classification of mental health disorders may have gone too far in a purely descriptive direction (overlapping categories, excessive co-morbidities, etc.), thereby compromising efforts to improve our understanding and treatment of psychopathology, he recommended that the classification of mental disorders also reflect the quality and degree of functional impairment and, where possible, etiology.

The mental health field has a long history of describing symptom patterns. As in the development of many fields, this effort began with pioneers who made meticulous observations and discovered common clusters of patient complaints, symptoms, and behaviors. In attempting to make progress in describing naturally occurring patterns, however, much recent research has been a mixed blessing. On the one hand, carefully constructed questionnaires and structured interviews have led to more reliable judgments about symptom patterns and have facilitated research into what belongs in a pattern, including its antecedents and course. On the other hand, fixed definitions (often made by clinical consensus) and incomplete data have impeded the improvement of descriptions of naturally occurring patterns.

A patient may experience a number of symptom patterns. Many such patterns have long been observed to overlap. In the DSM and ICD systems, the use of fixed definitions and strict criteria (e.g., four out of six, not three out of six, items on a diagnostic checklist) forces an artificial separation of conditions that are frequently related. Symptoms that may be etiologically, phenomenologically, or contextually interconnected are described as co-morbid conditions, as if these discrete problems coexist more or less accidentally in the same person, much as a sinus infection and a broken toe might coexist. Assumptions about discrete, unrelated, co-morbid conditions are rarely justified by compelling data such as clear genetic, biochemical, and neurophysiological distinctions between syndromes. The cut-off criteria for diagnosis are often arbitrary decisions of committees rather than conclusions drawn from the best scientific evidence.

The development of the PDM reflects our concern that mental health professionals may have uncritically and prematurely adopted methods from other sciences instead of developing empirical procedures appropriate to the complexity of the data in our field. The intent of those who moved the DSM and ICD classifications in the direction of specifying discrete, externally observable disorders was to build a stronger foundation for the diagnosis and treatment of psychopathology. This was a worthy project. Now, however, it is time to take a hard look at the phenomena with which mental health professionals regularly deal and adapt the methods to the phenomena rather than vice versa (see Part III, review essays by Blatt, Shedler, Westen).

The PDM attempts to do this. Because the current terminology for symptoms and their groupings comes from a long and intellectually serious tradition, we employ the descriptions of symptoms and patterns of symptoms used in the currently prevailing taxonomies, the DSM-IV-TR and ICD-10, systems that represent a valuable history of careful observation and description. In the most recent versions of the DSM and ICD systems, however, some of the more subtle features of many basic symptom patterns have been lost. Most notably, despite the fact that it is usually the patient's subjective suffering that brings him or her to treatment, a full description of the patient's internal experience of the symptoms is often absent.

All approaches to assessment and treatment rely at least in part on patients' reports of their thoughts, feelings, and behaviors. (Does the patient feel depressed? Anxious? Does the patient hear voices? Think about suicide?). Therefore, despite the fact that mental health professionals are always inevitably dealing with the elusive world of subjectivity, we require a fuller description of the patient's internal life to do justice to understanding his or her distinctive experience. We are hoping that with more elaborated depictions, we can make more progress on understanding naturally occurring patterns. The rapidly advancing neuroscience field, including genetic studies, can only be as useful as our understanding of the naturally occurring basic patterns of mental health and pathology. We cannot expect our colleagues in genetics to separate the apples and oranges for us. If we do not properly separate them, we will continue to frustrate the search for underlying biological pathways and common experiential etiologies.

Even in general medicine, instances in which etiological factors are fully understood are rare. Most commonly, we are at the level of functional rather than etiological explanation. Neoplastic disorders, for example, are often thought to be understood etiologically, but we are still searching for the causes of many malignancies, as we attempt to comprehend the relationship between genetic, environmental, and, in some instances, viral and other infectious processes. We are nonetheless able to describe various malignancies in detail in terms of their functional characteristics. Both in general medicine and in mental health, progress in understanding the functional nature of disorders should eventually facilitate a greater understanding of etiological factors. Functional and etiological understanding together provide the fullest basis for diagnosis and treatment.

In general, there is a healthy tension between the goals of capturing the complexity of clinical phenomena (functional understanding) and developing criteria that can be reliably judged and employed in research (descriptive understanding). It is vital to embrace this tension by pursuing a step-wise approach in which complexity and clinical usefulness influence operational definitions and inform research. A scientifically based system begins with accurate recognition and description of complex clinical phenomena and builds gradually toward empirical validation. Relying on oversimplification and favoring what is measurable over what is meaningful do not operate in the service of good science.

In addition , we are learning that when therapists apply manualized treatments to selected symptom clusters without addressing the complex person who experiences the symptoms and without attending to the therapeutic relationship that supports the treatment, therapeutic results are short-lived and rates of remission are high (Westen, Novotny, et al. 2004; Hilsenroth, Ackerman, et al. 2003; Baumann, Hilsenroth, et al. 2001; Stiles, Agnew-Davies, et al. 1998). A recent meta-analysis of outcomes of manualized treatments for targeted symptoms found that symptomatic improvement often did not persist and that fundamental psychological capacities involving the depth and range of relationships, feelings, and coping strategies did not show evidence of long-term change. In a number of studies these critical areas were not even measured (Westen, Novotny, et al. 2004).

At the same time, process-oriented research has demonstrated that essential characteristics of the psychotherapeutic relationship as conceptualized by psychodynamic models (the working alliance, transference phenomena , and stable characteristics of patient and therapist) are more predictive of outcome than any designated treatment approach per se . Most dynamically oriented clinicians pay careful attention to the therapeutic relationship, noting interpersonal patterns, feelings, coping strategies, and other indicators of mental processes. Although under-researched for decades, several recent meta-analyses and reviews reveal evidence of the efficacy of psychodynamically based treatments (see Part III review essays by Fonagy and Leichsenring, as well as Hilsenroth, Ackerman, et al. 2003; Leichsenring & Leibing 2003).

Although the psychoanalytic tradition, or depth psychology, has a long history of examining overall human functioning in a searching and comprehensive way, the diagnostic precision and usefulness of psychodynamic approaches have been compromised by at least two problems. First, until fairly recently, in attempts to capture the range and subtlety of human experience, psychoanalytic accounts of mental processes have been expressed in competing theories and metaphors that have, at times, inspired more disagreement and controversy than consensus. Second, there has been difficulty distinguishing between speculative constructs on the one hand, and phenomena that can be observed or reasonably inferred on the other. Where the tradition of descriptive psychiatry has had a tendency to reify "disorder" categories, the psychoanalytic tradition has tended to reify theoretical constructs.

In recent years, however, having developed empirical methods to quantify and analyze complex mental phenomena, depth psychology has been able to offer clear operational criteria for a more comprehensive range of human social and emotional conditions (see (Lingiardi, Shedler, et al. 2005, and Part III review essays by Blatt, Dahlbender, Westen, Shedler). The current challenge is to systematize these advances with a growing body of rich clinical experience in order to provide a widely usable framework for understanding and specifying complex and subtle mental phenomena.

A psychodynamically based system highlights the processes that contribute to emotional and social functioning. Early in its history, psychodynamic theories speculated about etiological factors. As in all fields of medicine, however, clinicians and researchers quickly learned that the etiologies of psychological disorders are more complex than initial observations and theory had suggested. Consequently, psychodynamic models have moved toward functional understanding of psychopathologies, with the expectation that such understanding will guide the identification of etiological patterns.

In light of all this, the PDM addresses the full range of mental functioning. Its approach to personality disorders identifies patterns that capture the quality and degree of impairment in such basic capacities as forming and sustaining relationships; regulating affects, moods, and impulses; and carrying out essential human functions in family, educational, and work settings. Its profile of mental functioning specifies components of these functional patterns. Its approach to symptom patterns is to add to the DSM descriptions an understanding of the patient's unique internal experience of his or her problems.

The PDM uses a multi dimensional approach to describe the intricacies of the patient's overall functioning and ways of engaging in the therapeutic process. It begins with a classification of the spectrum of personality patterns and disorders, then offer s a "profile of mental functioning" covering in more detail the patient's capacities, and finally considers symptom patterns, with emphasis on the patient's subjective experience.

Dimension I: Personality Patterns and Disorders

The PDM classification of personality patterns takes into account two areas: the person's general location on a continuum from healthier to more disordered functioning, and the nature of the characteristic ways the individual organize s mental functioning and engage s the world.

This dimension has been placed first in the PDM system because of the accumulating evidence that symptoms or problems cannot be understood, assessed, or treated in the absence of an understanding of the mental life of the person who has the symptoms. For example, a depressed mood may be manifested in markedly different ways in a person who fears relationships and avoids experiencing and expressing most feelings and in an individual who is fully engaged in all of life's relationships and emotions. There is not just one clinical presentation of the artificially isolated phenomenon known as depression.

Dimension II: Mental Functioning

The second PDM dimension offers a more detailed description of emotional functioning-the capacities that contribute to an individual's personality and overall level of psychological health or pathology. It takes a more microscopic look at mental life, systematizing such capacities as information processing and self-regulation; the forming and maintaining of relationships; experiencing, organizing, and expressing different levels of affects or emotions; representing, differentiating, and integrating experience; using coping strategies and defenses; observing self and others; and forming internal standards.

Dimension III: Manifest Symptoms and Concerns

Dimension III begins with the DSM-IV-TR categories and goes on to describe the affective states, cognitive processes, somatic experiences, and relational patterns most often associated clinically with each one. We approach symptom clusters as useful descriptors . Unless there is compelling evidence in a particular case for such an assumption, we do not regard them as highly demarcated biopsychosocial phenomena. In other words, we are taking care not to overstep our knowledge base. Thus, Dimension III presents symptom patterns in terms of the patient's personal experience of his or her prevailing difficulties. The patient may evidence a few or many patterns, which may or may not be related, and which should be seen in the context of the person's personality and mental functioning. The multi dimensional approach depicted in the following sections provides a systematic way to describe patients that is faithful to their complexity and helpful in planning appropriate treatments.

Reference List

Baumann, B. D., Hilsenroth, M. J., Ackerman, S. J., Baity, M. R., Smith, C. L., Smith, S. R. et al. (2001). The capacity for dynamic process scale: An examination of reliability, validity, and relation to therapeutic alliance. Psychotherapy Research, 11, 275-294.

Hilsenroth, M. J., Ackerman, S. J., Blagys, M. D., Baity, M. R., & Mooney, M. A. (2003). Short-term psychodynamic psychotherapy for depression: An examination of statistical, clinically significant, and technique-specific change. The Journal of Nervous and Mental Disease, 191, 349-357.

Leichsenring, F. & Leibing, E. (2003). The effectiveness of psychodynamic therapy and cognitive behavior therapy in the treatment of personality disorders: A meta-analysis. American Journal of Psychiatry, 1610, 1223-1232.

Lingiardi, V., Shedler, J., & Gazzillo, F. (2005). Assessing personality change in psychotherapy with the SWAP-200: A case study. under review.

McHugh, P. (2005). Commentary : Striving for Coherence: Psychiatry's Efforts Over Classification . Journal of the American Medical Association, 293, 2526-2528.

Norcross, J. C. (2002). Empirically supported therapy relationships. In J.C.Norcross (Ed.), Psychotherapy Relationships that Work: Therapist Contributions and Responsiveness to Patients (pp. 3-16). London : Oxford.

Spiegel, A. (2005). The dictionary of disorder: How one man revolutionized psychiatry. The New Yorker, 56-63.

Stiles, W., Agnew-Davies, R., Hardy, G. E., Barkham, M., & Shapiro, D. (1998). Relations of the alliance with psychotherapy outcome: Findings in the second Sheffield Psychotherapy Project. Journal of Consulting and Clinical Psychology, 66 , 791-802.

Wampold, B. E. (2001). The great psychotherapy debate - Models, methods and findings. Mahwah , NJ : Erlbaum.

Westen, D., Novotny, C. M., & Thompson-Brenner, H. (2004). The empirical status of empirically supported psychotherapies: Assumptions, findings, and reporting in controlled clinical trials. Psychological Bulletin, 130, 631-663.