The "prodromal" patient: both symptomatic and at-risk

This article discusses conceptual issues relevant to the prospective diagnosis of the schizophrenic prodrome. Recent efforts to diagnose these patients with operational criteria based on current symptoms are reviewed. Symptomatic patients so identified appear to be treatment-seeking and to have mild cognitive impairments. In addition to being currently symptomatic, these patients are imminently at risk for progression of illness and development of schizophrenia. Data from three international centers suggest that this risk is approximately 40% over the next year of follow-up if untreated. The implications of the reviewed data for the appropriateness of the term "prodromal" and for treatment/prevention research for these patients are discussed.     

Preventing clinical deterioration in the course of schizophrenia: the potential for neuroprotection

Schizophrenia, which has both genetic and environmental causes, is associated with persistent symptoms and severe functional disability. The illness lies dormant during the premorbid phase and begins to express itself during adolescence or early adulthood. Clinical progression and deterioration reaches a plateau in which the patient is said to be in the chronic phase of illness and at which point restoration of prior functioning is unlikely. The severe deficits associated with schizophrenia are often the result of progression of illness due to lack of appropriate treatment. However, recent advances in neuropsychiatry have led to very early identification of individuals at risk for psychosis, even during the prodromal stage when psychosis has not yet manifested clinically. While research has demonstrated that the efficacy of antipsychotics is limited when used during the chronic phase of illness, these medications can effectively control symptoms and prevent progression of illness when used during the early stages of illness. The evidence of neural degeneration in the pathophysiology of schizophrenic illness suggests that there may be treatment opportunities through neural protection. Neuroprotection, which refers to treatment that helps maintain central nervous system functionality in response to neurobiologic stress, may be responsible for prevention of disease progression and deterioration. In this monograph, Jeffrey L. Lieberman, MD, introduces the phases of schizophrenic illness in relation to the concepts of progression and deterioration. Next, Dolores Malaspina, MD, reviews the neurodevelopmental and neurodegenerative components of schizophrenia. Finally, L. Fredrik Jarskog, MD, focuses on the neuroprotective aspects of therapeutic interventions in schizophrenia.     

Movement abnormalities predict conversion to Axis I psychosis among prodromal adolescents

Evidence suggests that movement abnormalities are a precursor of psychosis. The link between movement abnormalities and psychotic disorders is presumed to reflect common neural mechanisms that influence both motor functions and vulnerability to psychosis. The authors coded movement abnormalities from videotapes of 40 adolescents at risk for psychosis (designated prodromal on the Structured Interview for Prodromal Symptoms; T. J. Miller et al., 2002). Following initial assessment, participants were evaluated for diagnostic status at 4 times annually. Ten participants converted to an Axis I psychosis (e.g., schizophrenia) over the 4-year period. Comparisons of converted and nonconverted participants at baseline indicated that the groups did not differ on demographic characteristics or levels of prodromal symptomatology, but those who converted exhibited significantly more movement abnormalities. Movement abnormalities and prodromal symptoms were strongly associated and logistic regression analyses indicated that abnormalities in the face and upper body regions were most predictive of conversion. Findings suggest that individuals with elevated movement abnormalities may represent a subgroup of prodromal adolescents who are at the highest risk for conversion. The implications for neural mechanisms and for identifying candidates for preventive intervention are discussed.     

Variability in fundamental frequency during speech in prodromal and incipient Parkinson's disease: a longitudinal case study

Nearly two centuries ago, first observed that a particular pattern of speech changes occur in patients with idiopathic Parkinson's disease (PD). Numerous studies have documented these changes using a wide variety of acoustic measures, and yet few studies have attempted to quantify any such changes longitudinally, through the early course of the disease. Moreover, no attempt has been made to determine if speech changes are evident during the prodromal period, prior to the onset of clinically noticeable symptoms. This case-control pilot study is a first attempt to determine if changes in fundamental frequency variability during speech, an acoustic measure known to be affected later in the course of the disease, are evident during the prodromal period. A retrospective analysis of videotape footage recorded and made available by a leading national television news service. Videotape samples were obtained for a single individual (and a well-matched control subject) over an 11-year period of this individual's life (7 years prior to diagnosis of PD, and 3 years post-diagnosis). Results suggest that changes in F0 variability can be detected as early as 5 years prior to diagnosis (consistent with findings from other laboratories that have relied on cross-sectional study approaches). This pilot study supports the utility of such a design approach, and these results warrant continued effort to better understand the onset of PD and sensitivity of measurement of voice acoustical changes during the prodromal period.     

Neuropsychological Contributions to the Early Identification of Alzheimer’s Disease

A wealth of evidence demonstrates that a prodromal period of Alzheimer’s disease (AD) exists for some years prior to the appearance of significant cognitive and functional declines required for the clinical diagnosis. This prodromal period of decline is characterized by a number of different neuropsychological and brain changes, and reliable identification of individuals prior to the development of significant clinical symptoms remains a top priority of research. In this review we provide an overview of those neuropsychological changes. In particular, we examine specific domains of cognition that appear to be negatively affected during the prodromal period of AD, and we review newer analytic strategies designed to examine cognitive asymmetries or discrepancies between higher-order cognitive functions versus fundamental skills. Finally, we provide a critical examination of the clinical concept of Mild Cognitive Impairment and offer suggestions for an increased focus on the impact of cerebrovascular disease (CVD) and CVD risk during the prodromal period of AD.     

Kafka,paranoic doubles and the brain: hypnagogic vs. hyper-reflexive models of disrupted self in neuropsychiatric disorders and anomalous conscious states

Kafka's writings are frequently interpreted as representing the historical period of modernism in which he was writing. Little attention has been paid, however, to the possibility that his writings may reflect neural mechanisms in the processing of self during hypnagogic (i.e., between waking and sleep) states. Kafka suffered from dream-like, hypnagogic hallucinations during a sleep-deprived state while writing. This paper discusses reasons (phenomenological and neurobiological) why the self projects an imaginary double (autoscopy) in its spontaneous hallucinations and how Kafka's writings help to elucidate the underlying cognitive and neural mechanisms. I further discuss how the proposed mechanisms may be relevant to understanding paranoid delusions in schizophrenia. Literature documents and records cognitive and neural processes of self with an intimacy that may be otherwise unavailable to neuroscience. To elucidate this approach, I contrast it with the apparently popularizing view that the symptoms of schizophrenia result from what has been called an operative (i.e., pre-reflective) hyper-reflexivity. The latter approach claims that pre-reflective self-awareness (diminished in schizophrenia) pervades all conscious experience (however, in a manner that remains unverifiable for both phenomenological and experimental methods). This contribution argues the opposite: the "self" informs our hypnagogic imagery precisely to the extent that we are not self-aware.     

Movement abnormalities and the progression of prodromal symptomatology in adolescents at risk for psychotic disorders

The link between movement abnormalities and psychotic disorders is presumed to reflect common neural mechanisms that influence both motor functions and vulnerability to psychosis. The prodromal period leading to psychotic disorders represents both a viable point for intervention and a developmental period that, if studied, could shed light on etiology; however, no published studies have examined the temporal progression of this link. A group with high levels of prodromal symptomatology (i.e., adolescents with schizotypal personality disorder [SPD]; n = 42) and both psychiatric controls (with other personality disorders or conduct disorder [OD]; n = 30) and nonpsychiatric controls ([NC]; n = 49) were recruited. Videotapes of structured psychiatric interviews were coded for movement abnormalities by raters blind to participants' diagnostic status, and follow-up assessments were conducted 1 year later. Controlling for psychotropic medications, the authors found that adolescents with SPD exhibited significantly more motor abnormalities in the face and upper body than did OD and NC controls. At baseline, movement abnormalities were positively correlated with the severity of positive, negative, and total prodromal symptoms. Within the SPD group, baseline movement abnormalities predicted symptom severity 1 year later. Movement abnormalities represent an early risk indicator that may be predictive of later symptom severity and potentially of psychosis onset.     

Historical origins of schizophrenia: two early madmen and their illness

Schizophrenia is a serious mental illness with a remarkably short recorded history. Unlike depression and mania, which are recognizable in ancient texts, schizophrenia-like disorder appeared rather suddenly in the psychiatric literature of the early nineteenth century. This could mean that the illness is a recent disease that was largely unknown in earlier times. But perhaps schizophrenia existed, embedded and disguised within more general concepts of madness and within the arcane languages and cultures of remote times. Both possibilities present major challenges to historical and psychiatric scholarship. These challenges are explored in this paper by presenting two "new" cases of schizophrenia, one from the eighteenth and one from the fourteenth century. The cases suggest that the illness may have existed as early as the medieval period. However, establishing the population prevalence of schizophrenia in earlier times--and therefore resolving the permanence-recency debate--may not be a feasible enterprise.     

Is there evidence that cognitive behaviour therapy is an effective treatment for schizophrenia? A cautious or cautionary tale?

Schizophrenia is a severe and disabling disorder with considerable psychological, social and economic costs. Over the last 15 years there has been a significant development in the use of cognitive behaviour therapy for psychosis (CBTp) in the treatment of schizophrenia, with 20 randomised controlled trials having been published. The majority of this work has been with alleviating medication resistant symptoms in chronic patients, but preliminary work has also been carried out with speeding recovery in acute schizophrenia and in relapse prevention and early intervention. A review of these studies indicates modest effect sizes, with the strongest evidence available for chronic patients. There is evidence that the effect size of the trials is significantly and negatively correlated to their methodological quality. We conclude cautiously that overall there is good evidence for the efficacy and effectiveness of CBTp in the treatment of schizophrenia.     

Relapse prevention for alcohol and drug problems: that was Zen, this is Tao

Relapse prevention, based on the cognitive-behavioral model of relapse, has become an adjunct to the treatment of numerous psychological problems, including (but not limited to) substance abuse, depression, sexual offending, and schizophrenia. This article provides an overview of the efficacy and effectiveness of relapse prevention in the treatment of addictive disorders, an update on recent empirical support for the elements of the cognitive-behavioral model of relapse, and a review of the criticisms of relapse prevention. In response to the criticisms, a reconceptualized cognitive-behavioral model of relapse that focuses on the dynamic interactions between multiple risk factors and situational determinants is proposed. Empirical support for this reconceptualization of relapse, the future of relapse prevention, and the limitations of the new model are discussed.     

Violent self-harm in schizophrenia

Patients with schizophrenia have a substantial lifetime suicide risk, especially by violent means. Little published work exists on self-harm (SH) in this population. The goal of this study was to examine whether patients with schizophrenia were also more likely to self-harm in a violent manner. A retrospective analysis performed on method, motive, and suicidal intent in patients with schizophrenia (n = 50) and adjustment reaction (n = 138) who presented with SH over a 3-year period found that there was no significant difference between the two groups in terms of violence of method or suicidal intent. Presence of positive symptoms of schizophrenia was not significantly associated with use of a violent method. This study suggests that the expected pattern of violent SH in schizophrenia is inaccurate and for the majority the acts are of a similar nature to those seen in adjustment reactions.     

The nature of schizotypy among multigenerational multiplex schizophrenia families

Identification of endophenotypes (Gottesman & Gould, 2003; Gottesman & Shields, 1972) that genetically correlate with schizophrenia and are genetically homogeneous is an important strategy for detecting genes that affect schizophrenia risk. Symptoms of schizotypy may familially correlate with schizophrenia; however, there are critical limitations of the current literature concerning this association. The present study examined the genetic architecture and genetic associations between schizotypy and schizophrenia among multigenerational, multiplex schizophrenia families. Genetic schizotypy factor scales were developed that genetically correlated with schizophrenia, although some relations were unexpected in direction suggesting minimization of "psychotic-like" symptoms. These genetic schizotypy factor scales did not genetically correlate with major depressive disorder or substance dependence indicating specificity to schizophrenia. The results highlight the possibility of significant response bias in schizophrenia families, particularly among close relatives, and suggest an important consideration when acquiring self-report information. This is a topic that deserves future study as the origins of this putative bias in relatives are unclear. In addition, the results support the identification of genetic schizotypy factors as a promising technique for maximizing genetic correlation of endophenotypes with schizophrenia.     

The timing of neurodevelopmental abnormality in schizophrenia: an integrative review of the neuroimaging literature

In this paper we will review recent neuroimaging research in schizophrenia, with an aim to critically evaluate several recent proposals concerning the nature and the timing of the neuroanatomic abnormalities underlying the disorder. Specifically, enlargement of cerebrospinal fluid spaces, deficits in cortical gray matter, and reduced volume of mesiotemporal structures have all been reported in patients in the first episode of schizophrenia, their first-degree relatives, and individuals with schizotypal personality disorder, supporting the possibility that these abnormalities reflect a genetically mediated neurodevelopmental disorder. These findings from the empirical literature will be synthesized from the perspective of dual cytoarchitectonic trends theory of neurodevelopment, as well as in relation to current conceptions of the schizophrenia prodrome. We believe that the evidence shows that sufficient groundwork has been laid to begin longitudinal neuroimaging studies of adolescents at clinical risk for schizophrenia, in order to more definitively determine the pathophysiology of the disorder. Such information could have significant implications in terms of understanding the prediction, treatment, and ultimately the prevention of schizophrenia.     

The use of pharmacotherapy in the prodrome of schizophrenia

In treating schizophrenia there has been a shift in focus, with more attention being paid to early intervention based on the notion that effective treatment at this point can improve outcome. Most of this work has centred on pharmacotherapeutic interventions during the first psychotic break. More recently, attention has turned to the potential value of intervening even earlier, that is during the so-called "prodrome" that has been identified as predating the first psychotic break by as much as 4-5 years. We now have a limited number of published reports addressing this topic and these are reviewed here.     

Applying a Transdiagnostic Cognitive-Behavioral Treatment to Adolescents at High Risk for Serious Mental Illness: Rationale and Preliminary Findings

Given the chronic and deleterious course of serious mental illness (SMI; schizophrenia and bipolar disorder), significant efforts have been undertaken to improve prediction of SMI and provide treatment for adolescents in the early, putatively prodromal stage of these illnesses. While risk assessments and disorder-specific treatments for adolescents at risk for SMI have shown some efficacy, significant issues remain around disorder-specific treatments for these youth. There is substantial heterogeneity of psychopathology within adolescents at high risk for SMI that leads to many false-positives and varying diagnostic outcomes. As a result, initial treatment focusing on broad symptoms and skills has been proposed in place of disorder-specific treatments. We discuss the rationale for providing an already-developed and empirically supported transdiagnostic treatment for emotional disorders (termed the Unified Protocol) as a first-line staging of treatment for adolescents experiencing early SMI symptoms. Additionally, we outline the open trial we are piloting using this transdiagnostic treatment in adolescents between the ages of 13 – 17 who have begun experiencing distressing yet subsyndromal psychosis or bipolar mood symptoms. Preliminary findings suggest feasibility and acceptability as well as initial efficacy in improving psychiatric symptoms, quality of life, and difficulties regulating emotions. We also present case studies from our open trial. A unified, cognitive-behavioral treatment for early presentations of SMI has important clinical and public health benefits, including streamlining treatment and providing broad skills that are applicable to a wide range of psychopathology.     

Cognitive-behavioural treatment of pathological gambling in individuals with chronic schizophrenia: a pilot study

The current study aimed to test the clinical effectiveness of a cognitive-behavioural program (CBT) specifically adapted for pathological gamblers with chronic schizophrenia, carried out in a naturalistic setting of community Mental Health Centres. Forty-four pathological gamblers with chronic schizophrenia were assigned either to a standard drug therapy for schizophrenia (control group) or to cognitive-behavioural therapy for pathological gambling plus a standard drug therapy for schizophrenia (experimental group). Psychological treatment comprised a 20-session program including psychoeducation, stimulus control, gradual exposure and relapse prevention. Therapeutic success was defined as abstinence or the occurrence of only 1 or 2 episodes of gambling during the follow-up period. While the patients treated in the experimental group showed a rate of success of 73.9%, only 19% of the participants belonging to the control group gave up gambling at the 3-month follow-up. The CBT group also did better than the control group in the number of gambling episodes and in the amount of money spent on gambling. However, the improvement of the experimental group was weaker at the 6- and 12-month follow-up. These findings support the beneficial effects of CBT as adjunctive therapy for patients with dual diagnoses (schizophrenia and pathological gambling).     

Dimensions of premorbid functioning in schizophrenia: a review of neuromotor, cognitive, social, and behavioral domains

After a brief discussion of methods for studying the premorbid period in schizophrenia, the authors review relevant experimental literature to assess the validity of current theories. A critical review is provided that includes representative empirical investigations on premorbid functioning in schizophrenia in the domains of neuromotor, intellectual, academic, cognitive, social, emotional, and behavioral functioning. Limitations of past research, such as lack of specificity to schizophrenia populations, high incidences of false positives, questionable definitions of the premorbid period, inconsistent measures of premorbid functioning, and problems with the current method of DSM classification are discussed. Alternative approaches to studying early functioning in schizophrenia are highlighted.     

Machiavellianism and Theory of Mind in people affected by schizophrenia

CONTEXT: People affected by schizophrenia show deficits in social interaction (Cramer, Bowen, & O'Neill, 1992); such a deficit may stem from an alteration in the representation of mental states. OBJECT: In this study we have examined 42 people affected by schizophrenia, diagnosed according to DSM-IV criteria, by testing them with an instrument (the Mach IV scale, Christie & Geis, 1970) assessing "Machiavellian Intelligence" according to Niccolò Machiavelli's assertions. Schizophrenic subjects were compared to a sample of normal controls, matched for age, sex, and education. OBJECTIVE: The aim of our study was to evaluate if there were correlations between the ability to understand other people's mental states and the capacity for interpreting "Machiavellian expressions." RESULTS: Results show that people affected by schizophrenia are less able to use Machiavellian-style "tactical" abilities than controls. CONCLUSION: Such a disability seems to be correlated to poor mentalising abilities.     

Context dependent latent inhibition in adult humans

Learning the association between one stimulus (a condition stimulus, CS) and another (unconditioned stimulus, US) can be impaired by prior exposure to the CS alone—latent inhibition (LI). Current theories attempting to elucidate the cognitive deficit in schizophrenia have used the abolition of LI in schizophrenia as an indicator of attentional dysfunction. However, it has always been unclear if human and animal LI are measuring the same psychological processes. It is obviously important to clarify this relationship so that theoretical and experimental developments in the rat do not mislead the investigation of brain-behaviour relationships in schizophrenia. LI in the rat is strongly dependent upon context. Our aim was to examine the context specificity of LI in humans and specifically to: (1) investigate whether participants' belief that they are in a different context is sufficient to abolish LI, even though there is no physical change in the environment; (2) produce a context manipulation that is immune to alternative interpretation in terms of stimulus generalization decrement; and (3) investigate whether a "tonic" change of context reduces or abolishes human LI, thus complementing previous reports using a "phasic" change of context. In two experiments we manipulated context in either the real world or a virtual world, and showed that LI is abolished by a change of context in adult humans.