John G. Csernansky

ERPs in schizophrenia: Effects of antipsychotic medication.

Thirty unmedicated schizophrenics were compared to 29 age-matched controls on auditory and visual event-related brain potential (ERP) paradigms. Twenty-one of these patients were tested again after 1 week on placebo and after 4 weeks on antipsychotic medication. Before treatment, N1, N2, and P3 components of the auditory ERP were smaller in the schizophrenics than in the controls. Although visual N2 was smaller in schizophrenics, visual P3 was not. In spite of significant clinical improvement with antipsychotic treatment, amplitudes of auditory and visual N1, N2, and P3 were not significantly changed. Higher blood levels of antipsychotic medication were related to reductions in auditory P3 latency, however. In addition, higher levels of cerebrospinal fluid (CSF) MHPG (methoxyhydroxyphenylglycol) were associated with larger auditory N1s and larger auditory and visual P3s, suggesting an influence of arousal on these components in schizophrenics. In spite of this influence, reduction of the auditory P3 in schizophrenia is an enduring trait of the disease, which is not affected by antipsychotic medication or clinical improvement.

Depression, parkinsonian symptoms, and negative symptoms in schizophrenics treated with neuroleptics.

To determine whether depression and neuroleptic-induced parkinsonism confound the clinical assessment of negative symptoms in schizophrenics, we evaluated 45 outpatient schizophrenics for depression, parkinsonian symptoms, and negative symptoms using standard clinical rating scales. Neuroleptic and anticholinergic dose and plasma activity were also determined. Associations between negative symptoms and these clinical and drug variables were examined using a multivariate statistical model. Negative symptoms were significantly correlated with several parkinsonian symptoms, some vegetative features of depression, and with anticholinergic dose. No significant correlations were found between negative symptoms and cognitive features of depression, or neuroleptic and anticholinergic plasma activity. These findings suggest that assessment criteria for negative symptoms, depression, and drug-induced parkinsonism overlap in treated schizophrenics. Strategies for differentiating these clinical syndromes are discussed.

Rating scales in research: The case of negative symptoms

Two measures of negative schizophrenic symptoms, the Scale for the Assessment of Negative Symptoms and the withdrawal-retardation subscale of the Brief Psychiatric Rating Scale, are found to be redundant when used together. Studies incorporating redundant measures have numerous disadvantages. Using multiple scales increases the cost and effort for the investigator, places a greater burden on research subjects, and compromises the interpretability of findings by increasing the probability of both Type I and Type II errors. A strategy for evaluating the use of multiple rating scales is suggested, and the theoretical basis of this strategy is discussed.

Dopaminergic Supersensitivity Follows Ferric Chloride-Induced Limbic Seizures

Injection of ferric chloride (FC) into the left amygdala of rats produced limbic seizures that lasted at least 3 weeks. In addition, FC-injected animals demonstrated motor impairment, decreased protesting vocalizations, and spontaneous stereotypies during a behavioral examination. An increase in apomorphine-induced stereotypies was also noted, and weekly administration of apomorphine for 3 weeks potentiated the increase in stereotypies produced by FC injection. These behavioral changes were associated with changes in postsynaptic dopamine D2 receptors. In animals injected only with FC, an increase in the [3H]-spiperone Bmax in the left nucleus accumbens and an increase in Kd in the right nucleus accumbens were noted. In FC-injected animals challenged weekly with apomorphine for 3 weeks, increases in the [3H]-spiperone Bmax in both amygdalae, the left nucleus accumbens, and the right nucleus caudatus and increases in Kd in the left amygdala and right nucleus accumbens were noted. Severance of the anterior commissure at the time of FC injection reversed most of these changes in behavior and dopamine receptor binding. Possible mechanisms for these changes are discussed, as well as the implications of these results for research on limbic dysfunction and psychopathology.

Symptomatology and cognitive impairment associate independently with post-dexamethasone cortisol concentrations in unmedicated schizophrenic patients

Serum cortisol concentrations were measured after dexamethasone administration (1 mg) in 21 neuroleptic-free schizophrenic inpatients. Patients were assessed using the Brief Psychiatric Rating Scale and a battery of cognitive tests. A significant correlation was found between negative symptoms and both 8:00 AM and 4:00 PM post-dexamethasone cortisol concentration (PDC). Cognitive impairment on several measures was also correlated with 8 AM PDC, but in an independent manner. Although positive and negative symptoms were unrelated, exploratory analysis revealed a significant inverse correlation between a positive symptom grouping and both 8:00 AM and 4:00 PM PDC.

Mesolimbic dopaminergic supersensitivity following electrical kindling of the amygdala

Limbic seizures developed in rats following daily electrical stimulation of the basolateral nucleus of the amygdala. Animals were designated as kindled after five complete (stage 5) behavioral seizures were observed. A subgroup, designated as superkindled, received three additional weeks of electrical stimulations. Kindled rats were significantly subsensitive to the stereotypy-inducing effects of apomorphine, a direct dopamine agonist, compared to controls. Superkindled rats were supersensitive to the effects of apomorphine. However, both kindled and superkindled rats demonstrated an increase in 3H-spiperone Bmax values, reflecting dopamine D2-receptor densities, in the nucleus accumbens ipsilateral to the stimulating electrode. The number of interictal spikes recorded from the stimulating amygdaloid electrode during the last week of kindling was correlated with changes in apomorphine sensitivity in individual animals.

Distinguishing depression and negative symptoms in unmedicated patients with schizophrenia

Depression can occur in schizophrenia but can be difficult to distinguish from negative symptoms of the illness. To evaluate whether concurrent use of the Hamilton Rating Scale for Depression (HRSD) and the Brief Psychiatric Rating Scale (BPRS) could successfully separate depression and negative symptoms, we examined ratings on 69 unmedicated schizophrenic inpatients. A classical BPRS depression subscale score correlated highly (rho = 0.80) with the HRSD total score. The classical BPRS negative symptom subscale score was unrelated to both the BPRS and HRSD depression summary measures. Among individual HRSD items, negative symptoms correlated only with work/activities and retardation. The findings suggest that negative and depressive symptoms may be assessed independently.

Mesolimbic dopamine receptor increases two weeks following hippocampal kindling

Kindled seizures developed in rats following repeated electrical stimulation of the left CA1 region of the hippocampus. Two weeks after the final kindled seizure, the densities of dopamine (DA) D2 receptors were assayed in the left and right amygdaloid area, nucleus accumbens, and nucleus caudatus. A significant increase (107%) in the density of DA D2-receptors in the ipsilateral nucleus accumbens occurred. This finding may help to define the long-term neurochemical consequences of kindling.

Sensitization versus tolerance to the dopamine turnover-elevating effects of haloperidol: the effect of regular/intermittent dosing

Recent clinical research suggests that particular patterns of changes in presynaptic dopamine (DA) turnover accompany the therapeutic response to neuroleptics. We sought to determine whether daily versus weekly dosing of haloperidol for 3 weeks produced distinct effects on DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) concentrations in multiple brain areas. Daily dosing favored the development of tolerance to the DA-turnover elevating effects of haloperidol in the striatum and nucleus accumbens. Weekly dosing favored the development of sensitization in the striatum, posterior olfactory tubercle, and ventral tegmental area. These results suggest that dosing schedules may determine, at least in part, the effects of chronic neuroleptic administration on presynaptic DA function.

Differences in the time course of dopaminergic supersensitivity following chronic administration of haloperidol, molindone, or sulpiride

The onset and persistence of changes in 3H-spiroperidol binding to dopamine (DA) D2 receptors were examined in rat mesolimbic and striatal regions following daily administration of haloperidol, molindone, or sulpiride for 3, 7, 14, or 28 days. Neuroleptic dose equivalencies were determined by inhibition of 3H-spiroperidol in vivo binding in several rat brain regions. Changes in locomotor and stereotyped responses to the specific DA D2 agonist quinpirole were examined 3 days after the last treatment dose. Haloperidol or molindone administration increased mean stereotypy scores and striatal DA D2 receptor densities throughout the 28-day treatment period. In contrast, mesolimbic DA D2 receptor densities were transiently increased and returned to control values after 28 days of haloperidol or molindone treatment. Sulpiride treatment increased mean stereotypy scores and striatal Bmax values, but had no effect on locomotion or mesolimbic dopamine receptor density. Additionally, the magnitude of change in the various measures of brain DA function varied among the three neuroleptic treatment groups. Results from this study suggest that mesolimbic and striatal brain regions differ in their response to long-term neuroleptic administration and that drug choice may influence the magnitude of neuroleptic-induced dopaminergic supersensitivity.