Opposite effects of high and low frequency rTMS on mood in depressed patients: relationship to baseline cerebral activity on PET.

BACKGROUND: Optimal parameters of rTMS for antidepressant efficacy in general, or within patients, have not been adequately delineated. METHODS: Using a double-blind, sham-controlled, cross-over design, 22 adult patients with treatment refractory major depression (n=9; bipolar disorder, depressed phase) were randomized to active rTMS (20-Hz or 1-Hz) or sham rTMS conditions and given 5 rTMS treatments per week for two weeks. Repetitive TMS was administered at 100% of motor threshold for 1600 pulses over the left prefrontal cortex using a figure-eight coil. Patients initially randomized to sham rTMS were then exposed to two weeks of active rTMS with each frequency under blinded conditions. Those who received active 20-Hz and 1-Hz rTMS were crossed over to the opposite frequency for two weeks. Improvement in Hamilton Depression ratings were assessed after each two-week treatment phase. PET imaging was used to evaluate the patient's baseline absolute regional cerebral activity (blood flow and metabolism) as potential predictor of clinical response. RESULTS: Changes in depression severity on 1-Hz and 20-Hz rTMS were inversely correlated. PET scans with baseline hypoperfusion (but not hypometabolism) were associated with better improvement on 20-Hz rTMS as predicted. LIMITATIONS: The magnitude of the clinical change with either frequency at 100% motor threshold was not robust, and larger studies with higher intensities of rTMS for longer durations of time should be explored. CONCLUSIONS: High and low frequency rTMS exerts differential effects on depressed mood within individual subjects. The brain activity predictors and correlates of an optimal antidepressant response to rTMS remain to be better defined.

Lack of adverse cognitive effects of 1 Hz and 20 Hz repetitive transcranial magnetic stimulation at 100% of motor threshold over left prefrontal cortex in depression.

OBJECTIVE: The potential therapeutic effects of repetative transcranial magnetic stimulation (rTMS) are being examined in various neuropsychiatric illnesses. This study assesses the cognitive performance of depressed patients receiving high or low frequency rTMS for 10 days. METHODS: 18 depressed patients participated in a randomized double-blind cross-over study exploring the antidepressant effects of 2 weeks (10 daily) of sham, 1 Hz, or 20 Hz rTMS administered over the left dorsolateral prefrontal cortex at 100% of motor threshold (MT). A subgroup completed a battery of cognitive tests at baseline and following each 2-week phase of treatment, and differences in performance were assessed using paired t -tests and were correlated with the degree of clinical improvement using Hamilton Depression Rating Scale scores. RESULTS: There were no major changes in cognitive test scores as a result of 10 days of either 1 Hz or 20 Hz rTMS. Moreover, any minor attenuations in cognition were not related to the degree of clinical improvement. CONCLUSIONS: Cognitive functioning in many domains following 2 weeks of 1 Hz or 20 Hz rTMS at 100% MT over the left dorsolateral prefrontal cortex in depressed patients is not disrupted.

Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder.

BACKGROUND: Functional brain imaging studies in unipolar and secondary depression have generally found decreased prefrontal cortical activity, but in bipolar disorders findings have been more variable. METHODS: Forty-three medication-free, treatment-resistant, predominantly rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy control subjects had cerebral glucose metabolism assessed using positron emission tomography and fluorine-18-deoxyglucose. RESULTS: Depressed bipolar disorder patients compared to control subjects had decreased global, absolute prefrontal and anterior paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus, right amygdala) metabolism. Degree of depression correlated negatively with absolute prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic subcortical metabolism. Increased normalized cerebello-posterior cortical metabolism was seen in all patient subgroups compared to control subjects, independent of mood state, disorder subtype, or cycle frequency. CONCLUSIONS: In bipolar depression, we observed a pattern of prefrontal hypometabolism, consistent with observations in primary unipolar and secondary depression, suggesting this is part of a common neural substrate for depression independent of etiology. In contrast, the cerebello-posterior cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic) suggests a possible congenital or acquired trait abnormality. The degree to which these findings in treatment-resistant, predominantly rapid-cycling patients pertain to community samples remains to be established.

A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders.

There is a pressing need for additional treatment options for refractory mood disorders. This controlled comparative study evaluated the efficacy of lamotrigine (LTG) and gabapentin (GBP) monotherapy versus placebo (PLC). Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind, randomized, crossover series of three 6-week monotherapy evaluations including LTG, GBP, and PLC. There was a standardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose (LTG 500 mg or GBP 4,800 mg). The primary outcome measure was the Clinical Global Impressions Scale (CGI) for Bipolar Illness as supplemented by other standard rating instruments. The mean doses at week 6 were 274 +/- 128 mg for LTG and 3,987 +/- 856 mg for GBP. Response rates (CGI ratings of much or very much improved) were the following: LTG, 52% (16/31); GBP, 26% (8/31); and PLC, 23% (7/31) (Cochran's Q = 6.952, df = 2, N = 31, p = 0.031). Post hoc Q differences (df = 1, N = 31) were the following: LTG versus GBP (Qdiff = 5.33, p = 0.011); LTG versus PLC (Qdiff = 4.76, p = 0.022); and GBP versus PLC (Qdiff = 0.08, p = 0.70). With respect to anticonvulsant dose and gender, there was no difference between the responders and the nonresponders. The agents were generally well tolerated. This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients. Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study.

Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients.

BACKGROUND: High (10-20 Hz) and low frequency (1-5 Hz) repetitive transcranial magnetic stimulation (rTMS) have been explored for possible therapeutic effects in the treatment of neuropsychiatric disorders. As part of a double-blind, placebo-controlled, crossover study evaluating the antidepressant effect of daily rTMS over the left prefrontal cortex, we evaluated changes in absolute regional cerebral blood flow (rCBF) after treatment with 1- and 20-Hz rTMS. Based on preclinical data, we postulated that high frequency rTMS would increase and low frequency rTMS would decrease flow in frontal and related subcortical circuits. METHODS: Ten medication-free, adult patients with major depression (eight unipolar and two bipolar) were serially imaged using (15)O water and positron emission tomography to measure rCBF. Each patient was scanned at baseline and 72 hours after 10 daily treatments with 20-Hz rTMS and 10 daily treatments with 1 Hz rTMS given in a randomized order. TMS was administered over the left prefrontal cortex at 100% of motor threshold (MT). Significant changes in rCBF from pretreatment baseline were determined by paired t test. RESULTS: Twenty-hertz rTMS over the left prefrontal cortex was associated only with increases in rCBF. Significant increases in rCBF across the group of all 10 patients were located in the prefrontal cortex (L > R), the cingulate gyrus (L >> R), and the left amygdala, as well as bilateral insula, basal ganglia, uncus, hippocampus, parahippocampus, thalamus, and cerebellum. In contrast, 1-Hz rTMS was associated only with decreases in rCBF. Significant decreases in flow were noted in small areas of the right prefrontal cortex, left medial temporal cortex, left basal ganglia, and left amygdala. The changes in mood following the two rTMS frequencies were inversely related (r = -.78, p <.005, n = 10) such that individuals who improved with one frequency worsened with the other. CONCLUSIONS: These data indicate that 2 weeks of daily 20-Hz rTMS over the left prefrontal cortex at 100% MT induce persistent increases in rCBF in bilateral frontal, limbic, and paralimbic regions implicated in depression, whereas 1-Hz rTMS produces more circumscribed decreases (including in the left amygdala). These data demonstrate frequency-dependent, opposite effects of high and low frequency rTMS on local and distant regional brain activity that may have important implications for clinical therapeutics in various neuropsychiatric disorders.

Emerging trends in the treatment of rapid cycling bipolar disorder: a selected review.

Recent evidence suggests that lithium therapy (even as supplemented by antidepressants and neuroleptics) is inadequate for the majority of patients with bipolar illness, and particularly those with rapid cycling. Valproate and carbamazepine have emerged as adjuncts and alternatives, but they, too, often require additional approaches with lithium, thyroid hormones, and other putative mood stabilizers, including nimodipine (and related dihydropyridine calcium channel blockers), lamotrigine, gabapentin, topiramate, and the atypical neuroleptics. Evaluating how these agents and the unimodal antidepressants are optimally applied and sequenced in the treatment of bipolar illness with its multiple subtypes, patterns and comorbidities will require much future investigation and the development of new methodological clinical trial approaches.

Comparative pharmacology of bipolar disorder and schizophrenia.

The treatment of acute mania and schizophrenia overlap considerably in terms of the typical and atypical neuroleptics, but begin to diverge with the recognized mood stabilizers for bipolar affective illness--lithium, carbamazepine, and valproate--which are substantially less effective in schizophrenia than in affective illness. Moreover, the L-type calcium channel blocker verapamil is reported to be effective in mania, but it may exacerbate schizophrenia. A series of new putative mood stabilizing anticonvulsants (such as lamotrigine, gabapentin, and topiramate) and possible second-messenger targeted treatments (tamoxifen and omega-3 fatty acids) deserve further study in both affective and schizophrenic syndromes. Repeated transcranial magnetic stimulation (rTMS) of the brain offers considerable promise in the treatment of a variety of neuropsychiatric syndromes, especially with preliminary evidence of frequency-dependent effects on regional cerebral blood flow. New insights about the potential neurotrophic effects of lithium and the gene transcriptional effects of other psychotropics offer exciting new targets for therapeutics and strategies for future clinical trials and therapeutic applications in both syndromes.

Quenching revisited: low level direct current inhibits amygdala-kindled seizures.

We have reported that low frequency stimulation (1 Hz for 15 min), applied after kindling stimulation of the amygdala, inhibited the development and expression of amygdala-kindled seizures, an effect we termed quenching. Subsequently, we discovered that this effect could only be achieved when certain stimulators were used that also emitted a low-level direct current (DC). The studies reported here indicate that DC, applied once daily for 15 min at intensities of 5-15 microA, produced an intensity-related attenuation of kindling development and an increase in the afterdischarge threshold. This effect persisted in some animals for at least 1 month after discontinuation of the DC. In fully kindled animals, a robust increase in seizure threshold and persistent seizure inhibition were also observed using 10 microA of DC administered for 14 days. These results clarify and extend our original findings of a quenching effect; however, the mechanisms by which low level DC induces quenching require further elucidation.

Lipofectin-facilitated transfer of cholecystokinin gene corrects behavioral abnormalities of rats with audiogenic seizures.

To evaluate the potential for lipofectin-mediated central nervous system gene transfer, the plasmid coding for cholecystokinin was administered intracerebroventricularly to rats, which have congenital audiogenic seizures and high responses to peripheral electric stimulation-induced analgesia. Previous studies had shown that low brain cholecystokinin levels may be the neurochemical variable of rat's audiogenic seizure and high responses to the analgesia because cholecystokinin is an anticonvulsant and anti-opioid neuropeptide. Gene transfer of cholecystokinin corrected the increased susceptibility to audiogenic seizures and the high responses to analgesia for about one week. Similar administration of plasmid expressing beta-galactosidase indicated that the vector mainly transfected ependymal cells lining the ventricle and pia mater cells. The increased cholecystokinin messenger RNA and immunoreactivity in the hippocampus following stereotactic intrahippocampal administration of cholecystokinin plasmid was also demonstrated with in situ hybridization and immunohistochemistry techniques. These results suggest that lipofectin-mediated gene transfer will be useful for studies of brain function, the modification of behavior and gene therapy for central nervous system disorders.

A speculative model of affective illness cyclicity based on patterns of drug tolerance observed in amygdala-kindled seizures.

In this article, we discuss molecular mechanisms involved in the evolution of amygdala kindling and the episodic loss of response to pharmacological treatments during tolerance development. These phenomena allow us to consider how similar principles (in different neurochemical systems) could account for illness progression, cyclicity, and drug tolerance in affective disorders. We describe the phenomenon of amygdala-kindled seizures episodically breaking through effective daily pharmacotherapy with carbamazepine and valproate, suggesting that these observations could reflect the balance of pathological vs compensatory illness-induced changes in gene expression. Under certain circumstances, amygdala-kindled animals that were initially drug responsive can develop highly individualized patterns of seizure breakthroughs progressing toward a complete loss of drug efficacy. This initial drug efficacy may reflect the combination of drug-related exogenous neurochemical mechanisms and illness-induced endogenous compensatory mechanisms. However, we postulate that when seizures are inhibited, the endogenous illness-induced adaptations dissipate (the "time-off seizure" effect), leading to the re-emergence of seizures, a re-induction of a new, but diminished, set of endogenous compensatory mechanisms, and a temporary period of renewed drug efficacy. As this pattern repeats, an intermittent or cyclic response to the anticonvulsant treatment emerges, leading toward complete drug tolerance. We also postulate that the cyclic pattern accelerates over time because of both the failure of robust illness-induced endogenous adaptations to emerge and the progression in pathophysiological mechanisms (mediated by long-lasting changes in gene expression and their downstream consequences) as a result of repeated occurrences of seizures. In this seizure model, this pattern can be inhibited and drug responsivity can be temporarily reinstated by several manipulations, including lowering illness drive (decreasing the stimulation current), increasing drug dosage, switching to a new drug that does not show crosstolerance to the original medication, or temporarily discontinuing treatment, allowing the illness to re-emerge in an unmedicated animal. Each of these variables is discussed in relation to the potential relevance to the emergence, progression, and suppression of individual patterns of episodic cyclicity in the recurrent affective disorders. A variety of clinical studies are outlined that specifically test the hypotheses derived from this formulation. Data from animal studies suggest that illness cyclicity can develop from the relative ratio between primary pathological processes and secondary endogenous adaptations (assisted by exogenous medications). If this proposition is verified, it further suggests that illness cyclicity is inherent to the neurobiological processes of episode emergence and amelioration, and one does not need to postulate a separate defect in the biological clock. The formulation predicts that early and aggressive long-term interventions may be optimal in order to prevent illness emergence and progression and its associated accumulating neurobiological vulnerability factors.

Differential regulation of basal and kindling-induced TRH mRNA expression by thyroid hormone in the hypothalamic and limbic structures.

It has previously been demonstrated that thyrotropin-releasing hormone (TRH) mRNA expression is dramatically increased in limbic structures including dentate gyrus granular layer, and pyriform, entorhinal and perirhinal cortices following amygdala kindling. Since thyroid hormone regulates TRH mRNA in the paraventricular nucleus of the hypothalamus (PVN), we investigated whether basal or kindling-induced TRH mRNA expression in limbic regions is also regulated by thyroid hormone. Hypo- and hyperthyroidism was induced by treating rats with 0.05% 6-n-propyl-2-thiouracil (PTU) (equivalent to approximately 30 mg/kg/day) or 0.9 microM 3,5,3'-triiodo-L-thyronine (T3) (equivalent to approximately 50 micrograms/kg/day), respectively, in their drinking water for 10 days before kindling and throughout the kindling procedure. Rats were sacrificed 4 h after their first stage 5 seizure. None of the thyroid hormone manipulations altered kindling development, or behavioral and electrographic after-discharge seizure durations. Pituitary TSH beta mRNA levels were significantly increased by PTU and suppressed by T3, but unaffected by kindling. In addition, in situ hybridization showed that PTU administration increased and T3 administration decreased TRH mRNA levels in the PVN, consistent with thyroid hormone's negative feedback effects. At the same time, kindling had no effect on TRH mRNA in the PVN. In contrast, kindling dramatically increased TRH mRNA in the dentate gyrus granular layer, and pyriform, entorhinal and perirhinal cortices, but thyroid hormone manipulations did not affect either basal or kindling-induced TRH mRNA expression in limbic structures. These findings demonstrate that TRH mRNA expression is differentially regulated in the hypothalamic PVN and limbic structures.

Rational polypharmacy in the bipolar affective disorders.

Bipolar affective illness represents a syndrome not readily treated by single agents. Approximately 50% of patients are inadequately responsive to lithium and the majority of patients require supplemental antidepressants, antimanic, antipsychotic or hypnotic medications. These traditional adjunctive medications are associated with potential problems. Antidepressants may precipitate mania (at a rate about double that of placebo) or cause cycle acceleration. Neuroleptics may be associated with either more profound or longer depressive phases, and clearly increase the risk of tardive dyskinesia, to which bipolar patients appear particularly predisposed. Moreover, there are subgroups of patients who are known to be poorly responsive to lithium. These include patients with rapid cycling, dysphoric mania, co-morbid drug or alcohol abuse, a pattern of depression-mania-well interval (D-M-I as opposed to the M-D-I pattern), and patients without a family history of bipolar illness in first-degree relatives. There is increasing recognition that the anticonvulsants carbamazepine and valproate are effective alternatives or adjuncts to lithium in the acute and long-term treatment of bipolar illness. Ideally, one would want to assess whether patients who were unresponsive to lithium were responsive to an anticonvulsant alone prior to utilizing lithium in addition to anticonvulsant combination therapy. However, from the clinical perspective, it is often more expedient to use an anticonvulsant adjunctively to lithium to assess the efficacy of this combination and establish mood stabilization. When lithium is not discontinued, the increased morbidity during lithium withdrawal also would not occur and would not confound the evaluation of the new agent. We suggest the initial use of acute adjuncts to lithium with the anticonvulsants carbamazepine or valproate (instead of neuroleptics) so that their efficacy can be assessed in the individual's acute episode, with the likelihood of a positive response in longer-term prophylaxis. Hypnotic benzodiazepines with anticonvulsant properties, such as clonazepam or lorazepam, are often used to help to induce sleep in escalating bipolar patients, and may be useful adjuncts as well. Patients who were inadequately responsive to either carbamazepine or valproate alone may be responsive to the anticonvulsant combination. In a similar fashion, one can also utilize several mood-stabilizing drugs (lithium and an anticonvulsant such as carbamazepine or valproate) in the treatment of depressive breakthroughs, and then augment this combination (if necessary) with a catecholamine-active antidepressant such as bupropion or a serotonin-selective reuptake inhibitor (SSRI) such as fluoxetine, paroxetine, sertraline or if necessary a monoamine oxidase inhibitor (MAOI). Once the patient has responded to a combination of drugs, it becomes problematic to decide whether the last agent added was the crucial ingredient in helping the patient achieve remission or that remission might have occurred with this agent alone. A conservative approach would have merit in patients who are finally stabilized on complex polypharmacy regimens only after many years of sequential trials; in this instance, the potential risk of re-exacerbating the illness with a taper of one of the drugs in the regimen. Rational polypharmacy should thus be implemented with careful delineation of the prior course of illness (typically using life chart methodology) and targeted treatment outcomes titrated against side effects, using sequential clinical trials in individual patients who have not adequately responded to monotherapy. In this fashion, it is hoped that pharmacodynamic differences among agents can be maximized and pharmacokinetic and side effects minimized.

Quenching: inhibition of development and expression of amygdala kindled seizures with low frequency stimulation.

Using low frequency (quenching) stimulation parameters (1 Hz for 15 min), similar to those that induce long-term depression (LTD) in vitro, we attempted to alter amygdala kindling in vivo in rats. Quenching completely blocked the development and progression of after-discharges and seizures in seven of eight animals. In fully kindled animals, once-daily quenching stimulation for one week (without concurrent kindling) suppressed the seizures when kindling stimulation was resumed. These effects of quenching probably resulted from the marked and long-lasting increases in the afterdischarge and seizure thresholds that were observed in these animals. These data indicate that quenching with low frequency electrical stimulation (which does not disrupt ongoing behavior) can have profound and long-lasting effects on seizure development, expression, and thresholds. The ultimate clinical applicability of low frequency stimulation in the treatment of seizures and related neuropsychiatric disorders remains to be explored.

Nimodipine increases CSF somatostatin in affectively ill patients.

Preliminary evidence suggests that nimodipine, an L-type calcium channel blocker, is effective in treating some patients with rapidly cycling affective disorders and some phases of Alzheimer's disease, i.e., two syndromes associated with transient or permanent reductions in cerebrospinal fluid (CSF) somatostatin, respectively. CSF somatostatin (SRIF) was measured in 14 affectively ill patients while they were medication-free and during chronic nimodipine treatment. CSF somatostatin significantly increased in patients during active nimodipine treatment compared with ones in the medication-free state. The current findings raise the possibility that nimodipine-induced increases in CSF somatostatin could potentially contribute to its spectrum of efficacy on neuropsychiatric disorders associated with cognitive or affective impairment. Further clinical and preclinical studies are indicated to elucidate the potential mechanisms involved in the elevation of CSF SRIF, whether it is reflected in regional changes in brain, and its possible relevance to nimodipine's clinical actions.

Effects of local anesthetics on experiential, physiologic and endocrine measures in healthy humans and on rat hypothalamic corticotropin-releasing hormone release in vitro: clinical and psychobiologic implications.

Local anesthetics, given i.v. to treat cardiac arrhythmias and for regional anesthesia, exert prominent central nervous system side effects, such as sensory distortions and mood changes. In experimental animals, these drugs activate limbic structures, such as the amygdala, that may coordinately regulate sensory processing, mood and pituitary hormone secretion during stress. Clinically relevant i.v. doses of the short-acting local anesthetic procaine were administered to 17 healthy volunteers and topographic electroencephalographic (EEG) spectra, stress-responsive neuroendocrine and cardiovascular parameters and sensory-cognitive and mood changes were examined. Because corticotropin-releasing hormone (CRH) mimics the behavioral and physiologic responses to stress and activates limbic structures in experimental animals, the effects of procaine and lidocaine on immunoreactive CRH release from rat hypothalami in vitro were also explored. Procaine administration produced a dose-related increase in fast (21-50 Hz) EEG activity, a significant decrease in alpha EEG activity and dose-dependent increases in heart rate, systolic blood pressure and plasma adrenocorticotropic hormone, cortisol and prolactin secretion. Dose-dependent increases in sensory distortions involved virtually all modalities, particularly auditory, visual and somatosensory. Mood changes occurred in most subjects, including anxiety, euphoria and arousal. In vitro, procaine and lidocaine both produced significant dose-related increases in immunoreactive CRH release from rat hypothalami, maximal at 10(-6) M, that were blocked by carbamazepine, a limbic anticonvulsant used in the management of mood disorders. The electrophysiologic effects of procaine in these volunteers were analogous to local anesthetic effects in experimental animals and consistent with the activation of subcortical structures localized within the temporal lobe, such as the amygdala. The effects of procaine on stress-responsive neurohormones were similar to those of amygdala stimulation both in experimental animals and human subjects. The in vitro data suggested that procaine-induced pituitary-adrenal activation involves stimulation of hypothalamic CRH, although additional (e.g., limbic-hypothalamic) mechanisms may contribute in vivo. These data were compatible with a direct action of local anesthetics on limbic structures that might account for many of the central effects seen with the systemic use of these agents in clinical practice.

Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation.

We report the initial results of the first controlled double-blind trial of nimodipine, a calcium channel antagonist, in the acute and prophylactic treatment of patients with treatment-refractory affective dysregulation. Active drug nimodipine (A) was substituted for placebo (B) in 12 patients. Patients were studied in a B-A-B design, with 3 of the 12 patients rechallenged with active drug in a B-A-B-A design (patients 9, 10, and 11). Five of the nine patients who completed the drug trial responded. One of three patients suffering from ultra-ultra-rapid (ultradian) cycling bipolar II disorder (patient 6) showed an essentially complete response; the other two ultradian patients (patients 4 and 9) showed evidence of a partial response on manic and depressive oscillations, one of which was confirmed in a B-A-B-A design. Only one of five less rapidly, but continuously cycling patients showed an excellent response (patient 10), and this was confirmed in a B-A-B-A design. The one patient who had recurrent brief depression (patient 11) showed a complete resolution of severe depressive recurrences, with response re-confirmed in an extended prophylactic trial with a B-A-B-A design. In the eight patients who completed self-ratings, nimodipine was associated with a significant reduction in the magnitude of mood fluctuations compared with the baseline placebo condition. Further clinical study of nimodipine, a calcium channel blocker with a unique profile of behavioral and anticonvulsant properties, appears warranted in patients with treatment-refractory affective illness characterized by recurrent brief depression and ultradian cycling.

Corticotropin-releasing hormone: potentiation of cocaine-kindled seizures and lethality.

Carbamazepine (CBZ) blocks the development of local anesthetic seizures kindled by cocaine and lidocaine. Cocaine and lidocaine release corticotropin-releasing hormone (CRH) in hypothalamic cell cultures, and this effect is also blocked by CBZ. Because CRH administered intracerebroventricularly (i.c.v.) can produce seizures, its potential role in the development of cocaine seizures and in the anticonvulsant effects of CBZ was studied. CRH (at doses of 5, 10, and 100 micrograms) potentiated cocaine-kindled seizure development and lethality in a dose-related fashion. CRH also reversed the effects of CBZ on cocaine kindling and lethality, but only at the highest doses, which also affected cocaine kindling. Thus, a selective role for CRH in the anticonvulsant effects of CBZ was not demonstrated. The findings suggest a potentially important role for CRH in exacerbating cocaine-seizure evolution and its associated lethality and confirm the inhibition of cocaine kindling and lethality by CBZ.

Evidence for hypothalamo-growth hormone dysfunction in panic disorder: profile of growth hormone (GH) responses to clonidine, yohimbine, caffeine, glucose, GRF and TRH in panic disorder patients versus healthy volunteers.

Given the abrupt and time-limited nature of daytime-awake and nocturnal-sleep panic attacks, several chemical and neuroendocrine challenge tests have been employed to investigate the neurobiology of "spontaneous" panic attacks. Previously we demonstrated that panic disorder patients have blunted growth hormone (GH) responses to clonidine, an alpha 2-adrenergic agonist. However, the mechanism of this blunted response and the role of hypothalamic-GH dysfunction, if any, remains unclear. To further delineate the status of hypothalamic-GH function in panic disorder, we review the literature and present original data on the GH responses to a number of different chemical and neuroendocrine challenge paradigms. Although stress-mediated increases in GH are thought to be a common correlate of stress in humans, our findings indicate that panic disorder patients have significantly blunted GH responses to clonidine, yohimbine, growth-hormone releasing factor, and caffeine compared to normal control subjects. A similar trend was noted in the delayed rise in GH after glucose challenge. There was no difference in the rate of abnormal GH responses to thyrotropin-releasing hormone in panic disorder compared to normal control subjects. No drug or neuroendocrine challenge, even if associated with marked increases in anxiety, produced a significantly enhanced GH response compared to normal control subjects. These findings provide support for a hyporesponsive hypothalamic-GH system in panic disorder. These observations, combined with preliminary observations from our clinic of short stature in several cases of prepubescent children with anxiety disorders, also underscore the need for assessing early growth patterns in individuals with panic disorder. Strategies for investigating the site(s) of possible neurotransmitter or hypothalamic-GH-somatomedin dysfunction are discussed.