Ten-year follow-up study of PTSD diagnosis, symptom severity and psychosocial indices in aging holocaust survivors.

OBJECTIVE: We performed a longitudinal study of holocaust survivors with and without post-traumatic stress disorder (PTSD) by assessing symptoms and other measures at two intervals, approximately 10 years apart. METHOD: The original cohort consisted of 63 community-dwelling subjects, of whom 40 were available for follow-up. RESULTS: There was a general diminution in PTSD symptom severity over time. However, in 10% of the subjects (n=4), new instances of delayed onset PTSD developed between time 1 and time 2. Self-report ratings at both assessments revealed a worsening of trauma-related symptoms over time in persons without PTSD at time 1, but an improvement in those with PTSD at time 1. CONCLUSION: The findings suggest that a nuanced characterization of PTSD trajectory over time is more reflective of PTSD symptomatology than simple diagnostic status at one time. The possibility of delayed onset trajectory complicates any simplistic overall trajectory summarizing the longitudinal course of PTSD.

Quantitative analysis of glutamate transporter mRNA expression in prefrontal and primary visual cortex in normal and schizophrenic brain.

Abnormalities of the glutamatergic system in schizophrenia have been identified in numerous studies, but little is known about the role of glutamate transporters and their messenger RNA (mRNA) expression. In addition, the abundances of the two major isoforms of human excitatory amino acid transporter 2 (EAAT2) or its rat ortholog, glutamate transporter 1, have never been compared in a quantitative manner. Using quantitative reverse transcription-polymerase chain reaction, we established that the expression of the EAAT1, EAAT2a, EAAT2b, and EAAT3 transcripts was not different in the dorsolateral prefrontal and primary visual cortices of persons with schizophrenia relative to matched controls. EAAT2a expression was about 25-fold and 10-fold higher than EAAT2b in human and rat brain, respectively. The data provided no evidence of an effect of antipsychotic medications on the mRNA expression of the glutamate transporters. However, because most of the schizophrenic subjects in the cohort had been treated with antipsychotics for many years, it is still possible that changes in transporter expression were masked by medication effects.

Clomipramine vs desipramine crossover trial in body dysmorphic disorder: selective efficacy of a serotonin reuptake inhibitor in imagined ugliness.

BACKGROUND: Body dysmorphic disorder (preoccupation with an imagined or slight defect in appearance) is a common and disabling disorder associated with high rates of delusional symptoms and suicide attempts. Although preliminary studies suggest that serotonin reuptake inhibitors may be effective for body dysmorphic disorder, to date no controlled treatment studies have been published. METHODS: Forty patients were enrolled and 29 were randomized into a 16-week, double-blind, crossover-design study of clomipramine, a potent serotonin reuptake inhibitor, and active control desipramine, a selective norepinephrine reuptake inhibitor. Outcome measures included specific ratings of body dysmorphic disorder severity, delusionality, and functional impairment. RESULTS: Clomipramine was superior to desipramine in the acute treatment of body dysmorphic disorder symptoms as measured by assessment of patients' obsessive preoccupation with perceived body defects, repetitive behaviors in response to this preoccupation, and global ratings of symptom severity. Treatment efficacy was independent of the presence or severity of comorbid diagnoses of obsessive-compulsive disorder, depression, or social phobia. Likewise, clomipramine was equally effective regardless of whether the patients had insight or held their dysmorphic misperception with delusional intensity. Clomipramine was also superior to desipramine in improving functional disability. CONCLUSIONS: Clomipramine is more effective than desipramine in the treatment of body dysmorphic disorder and is effective even among those patients who are delusional.

Patterns of risk in first-degree relatives of patients with Alzheimer's disease.

BACKGROUND: Although an increased cumulative risk for primary progressive dementia (PPD) has been repeatedly demonstrated in relatives of probands with Alzheimer's disease (AD), an examination of their rates of illness at different ages has not been previously undertaken. Such an examination might reveal possible age-related characteristics associated with a more familial variety of AD. METHODS: Using family history interviews and survival analysis, the cumulative risk for and 5-year age-specific hazard rates of PPD were assessed in the first-degree relatives of 200 probands with AD and two nondemented control groups--179 elderly ascertained through the Alzheimer's Disease Research Center (ADRC-derived controls) and 427 elderly ascertained from community senior centers (community controls). RESULTS: The PPD risk curve for the relatives of probands with AD rose to about 30% and was significantly higher than the curves for the relatives of the ADRC-derived and community controls, where comparable rates were observed (approximately 12%). The age-specific hazard rates of PPD were calculated in three groups of relatives for each 5-year interval from ages 45 to 49 years through ages 85 to 89 years. The age-specific relative risk (RRi) for PPD in the relatives of probands with AD began to steadily diminish from the 75- to 79-year age interval (RRi = 13.49) through the 85- to 89-year age interval (RRi = 0.96) compared with the relatives of ADRC-derived controls and from the 60- to 64-year age interval (RRi = 16.15) through the 85- to 89-year age interval (RRi = 2.03) compared with the relatives of the community controls. CONCLUSIONS: These data indicate that, for relatives of probands with AD, while the lifetime risk for PPD is greater than in relatives of controls, the familial contribution to the risk for PPD decreases with increasing age. The higher risk for PPD in relatives of probands with AD may be substantially diminished or even eliminated by the latter half of the ninth decade.

Eye tracking, attention, and schizotypal symptoms in nonpsychotic relatives of patients with schizophrenia.

BACKGROUND: Biological relatives of patients with schizophrenia demonstrate an increased prevalence of schizotypal personality disorder symptoms, eye tracking deficits, and attentional disturbances. We investigated whether these hypothesized components of a schizophrenia-related phenotype are associated with one another or are independent in nonpsychotic relatives of patients with schizophrenia. METHODS: Eighty-three nonpsychotic first-degree relatives of 38 patients with schizophrenia and 45 control subjects without a psychiatric diagnosis underwent clinical evaluation, eye tracking evaluation, and the Continuous Performance Test (CPT) of visual attention. RESULTS: Eye tracking qualitative rating was more powerful than quantitative eye tracking measures or CPT measures in discriminating relatives of patients with schizophrenia from control subjects. Correlations between neurocognitive variables and DSM-III-R schizotypal personality disorder symptom clusters suggested that CPT errors of omission are associated with positive schizotypal symptoms. Eye tracking measures were not significantly correlated with schizotypal symptoms or CPT errors in relatives of patients with schizophrenia. CONCLUSIONS: Eye tracking deficits in the relatives of patients with schizophrenia are unrelated to CPT deficits and schizotypal symptoms. Eye tracking deficits and disturbances in visual attention may be separate components of a schizophrenia-related phenotype and should be considered as independent factors in genetic studies of schizophrenia.

Limitations of controlled augmentation trials in schizophrenia.

To assess the empirical basis for add-on augmentation treatments in schizophrenia, this study examined the experimental design components of pharmacologic augmentation trials in schizophrenia and compared them to conventional requirements. A search covering a 5-year period (1988-1992) identified 13 double-blind, placebo-controlled, parallel, add-on neuroleptic augmentation drug trials. The mean number of subjects per trial was 34.5, and the mean number of outcome measures examined was 25.0. The probability for a significant finding by chance was 63%. Mean effect size required to achieve conventional statistical power was 1.6. Mean statistical power (for effect sizes of .5-1.0) was .1-.4. The mean number of subjects actually required for power of .80 was 58-216. The majority of the 13 trials included too few patients and employed too many outcome measures to conclusively prove or disprove therapeutic efficacy. Conclusions drawn from such trials with less than 40-100 subjects or more than one hypothesis must remain tentative at best.

Prolactin response to low-dose dexamethasone challenge in combat-exposed veterans with and without posttraumatic stress disorder and normal controls.

The prolactin and cortisol responses to dexamethasone (0.5 mg) were studied in combat veterans with (n = 18) and without (n = 12) posttraumatic stress disorder (PTSD) and normal controls (n = 18). Both veteran groups demonstrated greater prolactin suppression than the normals. In contrast, only veterans with PTSD showed an enhanced cortisol suppression in response to dexamethasone. These findings suggest that the prolactin response to dexamethasone may reflect a feature of combat exposure rather than PTSD per se.

Predictors of cortisol and 3-methoxy-4-hydroxyphenylglycol responses in the acute aftermath of rape.

BACKGROUND: Prospective studies of trauma survivors can provide information about the relationship between rape characteristics and the development of subsequent symptoms. METHODS: The present study examined the relationship of prior assault, rape severity, posttraumatic stress disorder (PTSD) symptoms following rape, and subsequent PTSD diagnosis, to the acute cortisol and 3-methoxy-4-hydroxyphenylglycol (MHPG) response to this traumatic event in 20 women. RESULTS: Women with a history of prior physical or sexual assault showed a significantly attenuated cortisol response to the acute stress of rape compared to women without such a history. MHPG appeared to be associated with injury-related rape characteristics, and symptoms of active avoidance, but not prior history. PTSD status at the 3-month follow-up was predicted by both a prior history of assault and high injury rape, but was not directly predicted by either cortisol or MHPG levels. MHPG and cortisol were not correlated in the sample as a whole, but were correlated among individuals who did not subsequently develop PTSD (p = .04) CONCLUSIONS: The results suggest that different neuroendocrine systems may mediate different components of the response to traumatic stress.

Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and clinical symptoms in Alzheimer's disease.

Postmortem findings point to significant abnormalities in central noradrenergic function in Alzheimer's disease (AD) which may be associated with changes in peripheral markers. In this study, the relationship between the peripheral noradrenergic marker, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), and clinical symptoms was examined in 23 patients with probable AD. Basal MHPG levels correlated significantly with increased cognitive impairment (r = .58, p = .005), controlling for age, age at onset, gender, and time interval between plasma MHPG determination and cognitive testing. These results suggest that plasma MHPG increases as cognitive function in AD deteriorates, further supporting preliminary evidence for increases in noradrenergic indices in association with disease severity in AD.

Plasma norepinephrine and 3-methoxy-4-hydroxyphenylglycol concentrations and severity of depression in combat posttraumatic stress disorder and major depressive disorder.

BACKGROUND: Catecholamines are thought to play a significant role in the pathophysiology of posttraumatic stress disorder (PTSD), but findings in PTSD have been discrepant. METHODS: To obtain more information about catecholamine activity in PTSD, we sampled plasma norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations over a 24-hour period in men with PTSD (n = 15) and major depressive disorder (MDD) (n = 12), and nonpsychiatric comparison subjects (n = 13), under unstimulated conditions. Chronobiological analyses were performed to determine possible changes in the circadian and ultradian release of these hormones. RESULTS: Significant group differences were present for mean plasma NE levels (p = .03), but not MHPG. NE levels were significantly associated with severity of depression in the PTSD group (p = .002). Therefore, PTSD subjects were further subdivided into those with and without a comorbid secondary depression. Increased NE levels were only present in PTSD subjects who did not have a secondary depression. This study also found no significant group differences on any of the chronobiological parameters. CONCLUSIONS: The results clarify that increased NE levels in PTSD may be confined to the subgroup of subjects who do not have comorbid depression, and as such, may help resolve some of the discrepancies in the literature regarding basal catecholamine activity.

Feeling unreal: cognitive processes in depersonalization.

OBJECTIVE: Depersonalization disorder is characterized by a detachment from one's sense of self and one's surroundings that leads to considerable distress and impairment yet an intact testing of reality. Depersonalized individuals often report difficulties in perception, concentration, and memory; however, data on their cognitive profiles are lacking. METHOD: Fifteen patients with depersonalization disorder were compared to 15 matched normal comparison subjects on a comprehensive neuropsychological test battery that assessed cognitive function. RESULTS: The subjects with depersonalization disorder showed a distinct cognitive profile. They performed significantly worse than the comparison subjects on certain measures of attention, short-term visual and verbal memory, and spatial reasoning within the context of comparable intellectual abilities. CONCLUSIONS: The authors propose that depersonalization involves alterations in the attentional and perceptual systems, specifically in the ability to effortfully control the focus of attention. These early encoding deficits are hypothesized to have a deleterious effect on the short-term memory system; they manifest as deficits in the ability to take in new information but not in the ability to conceptualize and manipulate previously encoded information.

The role of childhood interpersonal trauma in depersonalization disorder.

OBJECTIVE: In contrast to trauma's relationship with the other dissociative disorders, the relationship of trauma to depersonalization disorder is unknown. The purpose of this study was to systematically investigate the role of childhood interpersonal trauma in depersonalization disorder. METHOD: Forty-nine subjects with DSM-IV depersonalization disorder and 26 healthy comparison subjects who were free of lifetime axis I and II disorders and of comparable age and gender were administered the Dissociative Experiences Scale and the Childhood Trauma Interview, which measures separation or loss, physical neglect, emotional abuse, physical abuse, witnessing of violence, and sexual abuse. RESULTS: Childhood interpersonal trauma as a whole was highly predictive of both a diagnosis of depersonalization disorder and of scores denoting dissociation, pathological dissociation, and depersonalization. Emotional abuse, both in total score and in maximum severity, emerged as the most significant predictor both of a diagnosis of depersonalization disorder and of scores denoting depersonalization but not of general dissociation scores, which were better predicted by combined emotional and sexual abuse. The majority of the perpetrators of emotional abuse were either or both parents. Although different types of trauma were modestly correlated, only a few of these relationships were statistically significant, underscoring the importance of comprehensively considering different types of trauma in research studies. CONCLUSIONS: Childhood interpersonal trauma and, in particular, emotional abuse may play a role in the pathogenesis of depersonalization disorder. Compared to other types of childhood trauma, emotional maltreatment is a relatively neglected entity in psychiatric research and merits more attention.

Vulnerability to posttraumatic stress disorder in adult offspring of Holocaust survivors.

OBJECTIVE: There has been considerable controversy regarding the impact of the Holocaust on the second generation, but few empirical data are available that systematically document trauma exposure and psychiatric disorder in these individuals. To obtain such data, the authors examined the prevalence of stress and exposure to trauma, current and lifetime posttraumatic stress disorder (PTSD), and other psychiatric diagnoses in a group of adult offspring of Holocaust survivors (N=100) and a demographically similar comparison group (N=44). METHOD: Subjects were recruited from both community and clinical populations and were evaluated with the use of structured clinical instruments. Stress and trauma history were evaluated with the Antonovsky Life Crises Scale and the Trauma History Questionnaire, PTSD was diagnosed with the Clinician Administered PTSD Scale, and other psychiatric disorders were evaluated according to the Structured Clinical Interview for DSM-IV. RESULTS: The data show that although adult offspring of Holocaust survivors did not experience more traumatic events, they had a greater prevalence of current and lifetime PTSD and other psychiatric diagnoses than the demographically similar comparison subjects. This was true in both community and clinical subjects. CONCLUSIONS: The findings demonstrate an increased vulnerability to PTSD and other psychiatric disorders among offspring of Holocaust survivors, thus identifying adult offspring as a possible high-risk group within which to explore the individual differences that constitute risk factors for PTSD.

Low cortisol and risk for PTSD in adult offspring of holocaust survivors.

OBJECTIVE: The study examined the association between cortisol and putative risk factors for posttraumatic stress disorder (PTSD) in a sample of subjects at increased risk for the development of PTSD. METHOD: Twenty-four-hour urinary cortisol excretion was measured in 35 adult offspring of Holocaust survivors and 15 healthy comparison subjects who were not offspring of Holocaust survivors. Subjects were also characterized with regard to clinical symptoms, presence or absence of psychiatric diagnoses including PTSD, and presence or absence of PTSD in their parents. RESULTS: Low cortisol levels were significantly associated with both PTSD in parents and lifetime PTSD in subjects, whereas having a current psychiatric diagnosis other than PTSD was relatively, but nonsignificantly, associated with higher cortisol levels. Offspring with both parental PTSD and lifetime PTSD had the lowest cortisol levels of all study groups. CONCLUSIONS: Parental PTSD, a putative risk factor for PTSD, appears to be associated with low cortisol levels in offspring, even in the absence of lifetime PTSD in the offspring. The findings suggest that low cortisol levels in PTSD may constitute a vulnerability marker related to parental PTSD as well as a state-related characteristic associated with acute or chronic PTSD symptoms.

Impact of cumulative lifetime trauma and recent stress on current posttraumatic stress disorder symptoms in holocaust survivors.

OBJECTIVE: The purpose of this study was to examine the relationships among cumulative lifetime trauma, recent stressful events, and presence and severity of current posttraumatic stress disorder (PTSD) symptoms in Holocaust survivors and nonexposed comparison subjects. METHOD: Lifetime trauma, recent stressful events, and presence and severity of PTSD were assessed in Holocaust survivors (N=72) and comparison subjects ( N=19). RESULTS: Survivors with PTSD (N =40) reported significantly greater cumulative trauma and recent stress than survivors without PTSD (N=32) and comparison subjects. Severity of PTSD symptoms, cumulative trauma, and recent stress were significantly associated. CONCLUSIONS: The presence and severity of current PTSD were related to having experienced stressful events in addition to the Holocaust.

Relationship between posttraumatic stress disorder characteristics of Holocaust survivors and their adult offspring.

OBJECTIVE: There is controversy regarding the long-lasting effects of the Holocaust on the adult children of Holocaust survivors. In the present study the authors examined the relationship between posttraumatic stress disorder (PTSD) characteristics of Holocaust survivors and their adult children to determine whether differences in symptom severity or diagnostic status of parents would be associated with similar characteristics in their adult children. METHOD: Holocaust survivors (N = 22) and their offspring (N = 22) were interviewed with several instruments to assess lifetime trauma history, effect of trauma on one's life, level of intrusive and avoidance symptoms in response to reminders of the Holocaust, current and lifetime PTSD, and current and lifetime axis I psychiatric disorder other than PTSD. RESULTS: There were significant relationships between parents and children regarding the effect of trauma on one's life and level of intrusive, but not avoidance, symptoms in response to reminders of the Holocaust. Offspring with traumatic events were more likely to develop PTSD if their parents had PTSD. CONCLUSIONS: Symptoms in offspring may be related to presence and severity of symptoms in the parent. Furthermore, PTSD in the parent may be a risk factor for PTSD in offspring.

Clinical symptoms associated with age at onset in Alzheimer's disease.

OBJECTIVE: The aim of the study was to examine the relationship between age at onset of Alzheimer's disease and demographic and clinical characteristics in a large cohort of patients with Alzheimer's disease. METHOD: The subjects were 104 patients meeting the criteria for Alzheimer's disease of the National Institute of Neurological and Communicative Disorders and Stroke. The relationships of age at disease onset to cognitive and noncognitive variables and to rate of progression were explored by using multiple regression analysis. RESULTS: Earlier disease onset was associated with the presence of greater language and praxis difficulties and with the development of higher depression scores during the follow-up study period but not with faster disease progression. CONCLUSIONS: These findings suggest that in Alzheimer's disease, which is a clinically heterogeneous illness, younger age at onset may be related to the presence of more prominent language and praxis impairment and to development of greater depression during the disease course.

Feeling unreal: 30 cases of DSM-III-R depersonalization disorder.

OBJECTIVE: In contrast to the recent surge of interest in other dissociative disorders, DSM-III-R depersonalization disorder has not been thoroughly investigated and characterized. The authors systematically elucidated its phenomenology, comorbidity, traumatic antecedents, and treatment history. METHOD: Thirty adult subjects (19 women and 11 men) were consecutively recruited and administered various structured and semistructured interviews as well as the self-rated Dissociative Experiences Scale. An age- and sex-matched normal comparison group was also recruited. RESULTS: The mean age at onset of depersonalization disorder was 16.1 years (SD = 5.2). The illness had a chronic course that was usually continuous but sometimes episodic. Severe distress and high levels of interpersonal impairment were characteristic. Unipolar mood and anxiety disorders were common, but none emerged as specifically related to the depersonalization. A wide variety of personality disorders was manifested; avoidant, borderline, and obsessive-compulsive were most common. Although not highly traumatized, the subjects with depersonalization disorder reported significantly more childhood trauma than the normal comparison subjects. Depersonalization had been typically treatment refractory; only serotonin reuptake inhibitors and, to a lesser extent, benzodiazepines had been of any therapeutic benefit. CONCLUSIONS: This study supports the conceptualization of depersonalization disorder as a distinct disorder with a characteristic course that is independent of mood, anxiety, and personality symptoms. A subtle relationship may exist between childhood trauma and depersonalization disorder that merits further investigation. The disorder appears to be highly treatment refractory, and prospective treatment trials are warranted.

A longitudinal study of Alzheimer's disease: measurement, rate, and predictors of cognitive deterioration.

OBJECTIVE: This study measured the annual rate of cognitive change in patients with Alzheimer's disease and determined the effects of clinical variables on that rate. It also compared the ability of two cognitive scales to measure change over the entire range of dementia severity. METHOD: The cognitive subscale of the Alzheimer's Disease Assessment Scale and the Blessed test for information memory and concentration were given to 111 patients with Alzheimer's disease and 72 nondemented elderly comparison subjects at 6-month intervals for up to 90 months. Longitudinal changes in scores on the cognitive subscale were measured with several different methods of data analysis. RESULTS: For the patients with Alzheimer's disease, the annual rate of change in cognitive subscale scores showed a quadratic relationship with dementia severity in which deterioration was slower for mildly and severely demented patients than for patients with moderate dementia. Gender, age at onset, and family history of dementia had no effect on the rate of cognitive deterioration. The comparison group showed a slight improvement in cognitive performance over time. All data analytic methods gave similar results. The cognitive subscale of the Alzheimer's Disease Assessment Scale was more sensitive to change in both mild and severe dementia than was the Blessed test. CONCLUSIONS: These results suggest that cognitive deterioration is slow during the early and very late stages of Alzheimer's disease and more rapid during the middle stages. No clinical variables other than degree of cognitive impairment and previous rate of cognitive decline predicted rate of deterioration. These results have implications for treatment trials and attempts to identify subgroups.

Age at onset and familial risk in Alzheimer's disease.

OBJECTIVE: The authors investigated the relationship between probands' age at onset of Alzheimer's disease with the risk of primary progressive dementia in the probands' first-degree relatives. METHOD: Two hundred probands with clinically diagnosed Alzheimer's disease and 179 nondemented elderly probands were recruited from the Mount Sinai Alzheimer's Disease Research Center, located at Mount Sinai Hospital and the Bronx Veterans Affairs Medical Center. Demographic and diagnostic data were collected on 1,398 of the first-degree relatives of the probands with Alzheimer's disease and 955 first-degree relatives of the nondemented probands. RESULTS: Cox proportional hazards regression analysis showed a significant inverse relationship between age at onset of Alzheimer's disease in probands and greater familial risk in their relatives. Follow-up analyses indicated that the most commonly used age at onset cutoff point--65 years--was one of the points where an association with familial aggregation is least likely to be revealed; other onset cutoff ages (e.g., 55, 70, and 75) better identified Alzheimer's disease groups with differing familial/genetic risks. CONCLUSIONS: The authors conclude that patients with an earlier age at onset of Alzheimer's disease are more likely to have relatives with Alzheimer's disease than are patients with a later age at onset of the disease. An onset age of 70 best differentiated probands whose relatives were at higher risk from those whose relatives were at lower risk.