Comparability of blinded remote and site-based assessments of response to adjunctive esketamine or placebo nasal spray in patients with treatment resistant depression.

Functional unblinding due to treatment emergent adverse events (TEAEs) may occur with any investigational drug and poses a challenge for double-blind, placebo-controlled studies. This pilot study compared site-based Montgomery-Asberg Depression Rating Scale (MADRS) scores to remote, site-independent scores by blinded raters. Audio-digital recordings of site-based MADRS interviews were obtained from a subset of patients during a double-blind, placebo-controlled study of esketamine nasal spray or placebo spray in treatment resistant depression (Clinical Trials Registration: NCT01998958). Fourteen of 67 patients (21%) in the ITT population were randomly selected from 3 clinical trial sites. The site-based MADRS interviews were recorded at the baseline and 2 h post-dose assessments on the first intranasal dosing day. Site-independent raters scored the recordings and were blinded to treatment and all reported TEAEs, including any transient dissociative/perceptual symptoms. None of the 7 placebo-assigned patients achieved a treatment response or remission at the 2-h post-dose assessment. Four of the 7 esketamine-assigned patients (57.1%) achieved a treatment response at 2-h post-dose, and 3 patients (42.9%) achieved remission. Three esketamine-treated patients experienced transient dissociative symptoms. The remote site-independent raters essentially replicated the site-based MADRS scores and yielded a 92.9% predictive value for matching treatment response and remission rates. This small pilot study affirms that blinded remote ratings (without the likelihood of functional unblinding) are comparable to site-based ratings of efficacy of esketamine nasal spray. The audio-digital recording method offers a reasonable strategy for other studies that may also be vulnerable to functional unblinding due to distinctive TEAEs.

The risks associated with short-term placebo-controlled antihypertensive clinical trials: a descriptive meta-analysis.

Short-term (4-8 weeks) placebo-controlled trials are used to evaluate new antihypertensive drug treatment. To evaluate the consequences of such practice, a descriptive meta-analysis was conducted, consisting of blinded review of original case report forms for all patients who died or left a study before its completion for all short-term, placebo-controlled hypertension trials submitted to the Food and Drug Administration from 1973 through 2001. There were 93 marketing applications or supplements involving 590 individual trials that involved 86137 randomized patients (64438 randomized to experimental drug and 21 699 randomized to placebo) with 12658 patient years of observation. There were 9636 dropouts (mean time to dropout was 28 days) and relative risk (RR (placebo/drug))= 1.33 (95% confidence limits, 1.28, 1.39; P < 10(-16)). As expected, lack of blood pressure (BP) control was far more common in patients randomized to placebo; therapeutic failure, RR = 2.53 (2.35, 2.73; P < 10(s15)) and hypertensive emergency, RR = 2.75 (2.19, 3.57; P < 10(-15)). When administrative dropouts and dropouts resulting from inadequate BP control were excluded, the remaining 38% of dropouts were disproportionately more from drug (2810 drug, 816 placebo), RR = 0.80 (0.74, 0.86; P < 10(-8)). There were 43 deaths, RR=0.72 (0.33, 1.45; P=0.37); 40 strokes, RR = 1.43 (0.68, 2.81; P=0.33) and 77 myocardial infarctions, RR=1.06 (0.62, 1.75; P= 0.82). Irreversible harm (a combination of death, stroke and myocardial infarction, 160 total events) was equally distributed between the drug and placebo groups, RR=1.03 (0.71, 1.47; P=0.86).

Color blindness not closely linked to bipolar illness. Report of a new pedigree series.

A new pedigree series of bipolar manic-depressive patients admitted to the National Institute of Mental Health intramural research program was evaluated for linkage between bipolar illness and red-green color blindness, since previous studies had indicated that close linkage was generally present. Using family study methods, six informative pedigrees were investigated. Analysis was performed using a multigenerational procedure and taking into account variable penetrance. Close linkage could be definitively ruled out as a general finding. Bipolar and related illnesses are thus not generally transmitted by a single major gene close to the protan/deutan region of the human X-chromosome.

New data do not suggest linkage between the Xg blood group and bipolar illness.

The Xg blood group antigen (a genetic marker of a region of the X chromosome at a considerable distance from protan/deutan color blindness) was studied for linkage to bipolar manic-depressive illness. A multigenerational analytic method, taking variable penetrance into account, was used. In our series of six informative pedigrees, very close linkage could be definitively ruled out, and the likelihood of less tight linkage was consistently less than the likelihood of nonlinkage.

The Family Attitudes Questionnaire. Patients' and spouses' views of bipolar illness.

A newly devised Family Attitudes Questionnaire has been employed to quantify the perceptions of 19 bipolar manic-depressive patients and their well spouses about the etiology, familial risk, and long-term burden of bipolar illness, and to assess their abilities about marriage and childbearing. In this study, 53% of well spouses compared with 5% of patients (P less than .01) would not have had children if they had known more about bipolar illness prior to making these decisions. The overall data suggest that the bipolar patients, compared with his or her spouse, minimizes the burden and denies the heritable/familial nature of affective illness. These findings should be borne in mind for genetic counseling as well as for psychotherapy.

Computed tomography in schizophreniform disorder and other acute psychiatric disorders.

To assess whether computed tomographic findings are present at the onset of schizophrenia, we evaluated CT scans of 35 patients with first-episode schizophreniform disorder, 17 with chronic schizophrenia, 23 with affective disorders, 27 with other psychiatric disorders, and 26 controls. Both the schizophreniform and the chronic schizophrenic patients had significantly larger cerebral ventricles than did the other psychiatric or control subjects. Ventricular size in the patients with affective disorder was not significantly different than in any of the other groups. Twenty percent of the schizophreniform patients had enlarged ventricles, (ventricular-brain ratio, greater than 10). The only other subjects outside this limit were four chronic schizophrenic patients (24%). Five schizophreniform patients and three with affective disorder had evidence of mild cortical atrophy. The results suggest that, in some schizophrenic patients, ventricular enlargement and less frequently cortical atrophy predate the onset of psychoses and are not a result of psychiatric treatment.

A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands.

In a family study of 1,254 adult relatives of patients and controls, lifetime prevalences of major affective disorder (including schizoaffective) were 37%, 24%, 25%, 20% and 7% in relatives of probands with schizoaffective, bipolar I, bipolar II, and unipolar disease, and normal controls. These data were compatible with the different affective disorders representing thresholds on a continuum of underlying multifactorial vulnerability. In this model, schizoaffective illness represents greatest vulnerability, followed by bipolar I and bipolar II, then unipolar illnesses. Alcoholism, drug abuse, and sociopathy were not more frequent in relatives of patients v relatives of controls. Sex-related transmission of morbid risk was not present. Morbid risk was 74% to offspring of two III parents, and 27% to offspring of one III parent. Nationality and age at time of interview seem to be nongenetic factors that affect frequency of diagnosis.

Differential responses to anxiogenic challenge studies in patients with major depressive disorder and panic disorder.

Anxiogenic challenge studies (intravenous lactate infusion and oral fenfluramine challenge) were conducted in 17 patients with panic disorder (PD), 12 patients with major depressive disorder and a history of panic attacks (MDD-PD), 27 patients with major depression and no history of panic (MDD), and 12 normal controls. PD and MDD-PD patients revealed significantly greater anxiogenic responses to lactate infusion and fenfluramine administration than either MDD patients or controls. PD patients revealed the most robust anxiogenic responses to both challenges as well as associated significant prolactin and cortisol responses to fenfluramine. The findings suggest that the predisposition to panic attacks as seen in PD and MDD-PD patients may represent a distinct neurobiological diathesis which may coexist with a major depressive diathesis in some patients. The delineation of subgroups within the more heterogenous groups of patients with MDD and/or PD will lead to greater precision in the development of clinical treatment strategies. Thus, MDD-PD patients (better called panic-depressives) may have a more severe illness than patients with MDD alone which must be accounted for in the course of pharmacotherapy and psychotherapy.

The application of serial neuroendocrine challenge studies in the management of depressive disorder.

This paper describes the use of serial neuroendocrine challenge studies in the assessment of depressive disorder, specifically the dexamethasone suppression test (DST) and thyrotropin-releasing hormone (TRH) stimulation test. The combined use of these challenge tests revealed high sensitivity (67%) and high predictive value for the identification of endogenous depression in contrast to schizophrenia (p less than 0.025) or nondepressed patients (p less than 0.005). Further, normalization or persistence of dysregulation of these tests was correlated with clinical outcome at 6 months. Normalization of the DST occurred in 26 of 32 patients (82%) and was significantly correlated with the timing of symptomatic improvement (p less than 0.01). Five of six patients (84%) who never normalized the DST suffered an early relapse in contrast to 4 of 26 patients who did normalize (p less than 0.005). Unlike the DST, normalization of the blunted thyrotropin (TSH) response to TRH injection was not significantly correlated with the timing of symptomatic improvement. Only 8 of 19 patients (42%) ever normalized the TSH response. However, none of these 8 normalized patients suffered relapse within 6 months in contrast to 7 of 11 patients (64%) who did not normalize (p less than 0.025). Thus, failure of normalization of either the DST or TRH test was associated with a group of patients at high risk for early relapse. In this study, the use of prophylactic antidepressant medications did not avert relapse in 9 of 11 relapsed patients who had persistent neuroendocrine dysregulation.

Persistent neuroendocrine dysregulation in major depressive disorder: a marker for early relapse.

Neuroendocrine challenge studies, including the dexamethasone suppression test (DST) and thyrotropin-releasing hormone (TRH) stimulation test, were administered to 86 patients meeting DSM-III criteria for major depressive disorder. Of 33 patients, 25 (76%) revealed normalization of abnormal DSTs at the time of symptomatic improvement, and 9 out of 26 patients (35%) revealed normalization of blunted TSH responses to TRH injection. Patients with normalized function revealed treatment responsiveness and low relapse rates (11%) similar to patients who had had normal neuroendocrine function at the time of admission. However, 11 of 23 patients with persistent dysregulation on either test (48%) relapsed within 6 months in contrast to 3 of 28 patients with normalized function (p less than 0.01) and 5 of 35 patients with normal neuroendocrine function on admission (p less than 0.02). These findings suggest that persistent dysregulation may be a valuable prognostic marker reflecting partial treatment responsiveness in some patients which predisposes them to early relapse. Both the DST and TRH tests appear to reflect neuroendocrine trait deficits which are independent of but interact with a coexisting predisposition to depressive disorder.

Variability of TRH test responses in depressed and normal elderly subjects.

Thyrotropin releasing hormone (TRH) tests were conducted in 33 elderly patients with Major Depressive Disorder and 99 normal elderly volunteers. A wide range of thyrotropin-stimulating hormone (TSH) responses to TRH injection was revealed. A gender effect was found such that men had significantly diminished TSH responses to TRH relative to women (p = 0.008). However, there were no significant differences noted between depressed patients and normal elderly subjects of either gender. It appears that the wide range of TSH responses to TRH found in normal elderly men and women blurs any measurable differentiation between depressed patients and normal subjects and thereby limits the usefulness of the TRH test in the study of depressive disorder in elderly patients.

Human leukocyte antigen system not closely linked to or associated with bipolar manic-depressive illness.

An association and linkage study of the HLA system and bipolar affective illness is reported. HLA B-14 showed an increased frequency and HLA-Bw27 a decreased frequency in 92 bipolar patients compared to 210 controls, but significance is not reached when appropriate statistical corrections are made. It is shown that ethnological differences can lead to sampling biases; a purported increased frequency of HLA-Bw 16 in Ashkenazi Jewish bipolar patients is negated when ethnologically similar controls are used. The transmission of HLA alleles in nine families with at least two generations of affective illness revealed independent assortment, and nonlinkage to either locus A or B was demonstrated using a multigenerational method of linkage analysis. The nonreplicability of the HLA association studies, and the failure to demonstrate linkage of the HLA loci with afe development of affective illness, although further analyses are necessary.

Cognitive functioning in biological subtypes of depression.

This study describes a method for investigating clinical correlates of biological subtypes of depression, using cognitive functioning as the principal behavioral variable. Dexamethasone Suppression Test (DST) escapers were compared to DST suppressors and healthy controls on a battery of learning and memory procedures designed to investigate cognitive functioning in detail. DST suppressors, but not escapers, were cognitively impaired on our tasks. The performance of controls and DST escapers was related to depth of semantic processing, whereas performance of DST suppressors varied inversely with degree of felt hopelessness. Examination of cognitive functioning in future studies may provide useful insights into the clinical significance of biological markers of depression.

Lymphocyte subpopulations in depressed elderly women.

Dexamethasone Suppression Tests (DST) and measurement of lymphocyte subpopulations were conducted in 21 medically healthy elderly women with major depressive disorder and 77 healthy elderly women volunteers. Depressed women revealed significantly reduced absolute lymphocytes (p less than 0.01), T cells (p less than 0.01), and T helper cells (p less than 0.02) compared to normal elderly women. Of the depressed women, 50% had positive DSTs (postdexamethasone cortisols greater than 5 micrograms/dl) compared to 5.4% of the normal women (p less than 0.0001). Within the depressed group, patients with positive DSTs had significantly reduced absolute lymphocytes (p less than 0.05) and T helper cells (p less than 0.025) compared with depressed women who had normal DSTs. Further, a significant negative correlation was found between postdexamethasone cortisols (at both 4:00 and 11:00 PM) and absolute lymphocyte count and T helper cells. These data suggest that the hypercortisolemia seen in some patients with major depressive disorder is sufficient to alter leukocyte distribution in the peripheral circulation, particularly that of the T helper cell subset. The association between cortisol and lymphopenia appears to be more pronounced in an elderly population than in younger depressed patients.

Screening for PKU heterozygosity in bipolar affectively ill patients.

There were no significant differences noted between bipolar manic-depressive patients and normal controls for plasma phenylalanine or tyrosine following an L-phenylalanine loading test given to determine if some affective illness may be related to the heterozygous phenotypic expression of phenylketonuria (reduced liver phenylalanine hydroxylase). The test was able to distinguish known PKU heterozygotes from the other subjects. It is possible that other heterozygous states may be implicated in the development of some psychiatric disorders.

Cerebral ventricular size in major depressive disorder: association with delusional symptoms.

Computerized tomograms (CT scans) and neuroendocrine challenges (TRH stimulation test and dexamethasone suppression test) were completed in 38 melancholic depressed hospitalized patients. There were no significant differences in ventricular size between delusional and nondelusional depressives. However, 5 of 20 delusional depressives (25%) in contrast to none of 18 nondelusional depressives had ventricular brain ratios greater than 2 standard deviations from the mean of 26 neurological controls. There were no demographic, clinical, or neuroendocrine differences between patients with enlarged ventricles and those with normal CT scans. Two of 5 patients with large ventricles were rehospitalized within the 1st year of ascertainment in contrast to 3 of the other 15 delusional depressed patients. The possible relevance of cerebral ventricular size for depressive disorder is discussed.

Neuroendocrine dysfunction in schizophreniform disorder: correlation with six-month clinical outcome.

The thyrotropin-releasing hormone (TRH) stimulation test and the dexamethasone suppression test (DST) were administered to 21 patients with schizophreniform disorder at the time of admission for acute illness: 9 showed dysregulation on one or the other test. Seventeen patients followed for 6 months were divided into two groups: those with persistent dysfunction and/or psychotic symptoms and those in full remission. Only 1 of 7 patients (14%) with persistent dysfunction in contrast to 7 of 10 patients (70%) in full remission revealed dysregulation on either test. Neuroendocrine challenges may be useful in the early assessment of first-break psychotic patients, and neuroendocrine dysregulation may be a predictor of episodic illness with a better prognosis.

The dexamethasone suppression test in adolescent psychiatric inpatients.

The dexamethasone suppression test (DST) was administered to 120 adolescent psychiatric patients at the time of hospitalization, and cortisol levels were measured at 4:00 p.m. and 11:30 p.m. on the day after a 1-mg oral dose of dexamethasone was given. Failure to suppress serum cortisol (i.e., cortisol level less than 5 micrograms/dl) was noted in 25 patients: 7 of 17 patients who met DSM-III criteria for major depressive disorder, 7 of 38 patients with dysthymic disorder, 7 of 47 patients with conduct disorder, and 4 of 15 schizophreniform patients. The predictive value of the DST for major depressive disorder was only 28%. Although adolescent patients with abnormal DSTs may eventually develop affective symptoms consistent with a major depressive disorder, the DST did not discriminate between major depression and other psychiatric diagnoses in these hospitalized adolescents.

The dexamethasone suppression test in suicidal patients with unipolar depression.

Of 49 newly hospitalized patients who met Research Diagnostic Criteria for primary unipolar depression and were given the dexamethasone suppression test (DST), significantly more patients admitted for suicide attempts than nonsuicidal patients had abnormal DSTs. All five patients who made subsequent suicide attempts (one completed) within 6 months after admission had had abnormal DSTs. These findings suggest that the tendency of endogenously depressed patients to attempt suicide is exacerbated by an underlying neurobiological disorder reflected by limbic-hypothalamic dysregulation and that depressed suicidal patients with abnormal DSTs represent a high-risk group for recurrence of suicidal behavior.

An intervention to reduce the rate of hospital discharges against medical advice.

The initiation of a patient advocacy program in a private psychiatric hospital in 1980 was effective in significantly reducing the rate of hospital discharges against medical advice relative to the rate in 1979 and in 1978. There was also a concomitant increase in the rate of clinically approved discharges relative to that in 1979 and in 1978. The authors view the patient advocate as an objective intermediary who represents an acknowledgment of patients' rights and affords patients an opportunity to have some autonomy and an impact on the hospital system.