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Biomedical subjects

R M Post

Publications and source records attributed to R M Post.

At least 19 recordsLinked to original sources
PubMed1999

Venlafaxine but not bupropion decreases cerebrospinal fluid 5-hydroxyindoleacetic acid in unipolar depression.

BACKGROUND: While the antidepressants venlafaxine and bupropion are known to have different neurochemical profiles in vitro, their effects on human cerebral metabolism in vivo have not been directly compared. METHODS: Cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), serotonin, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were examined in 14 never-hospitalized outpatients with unipolar depression and 10 age-similar healthy controls. Patients received a baseline lumbar puncture (LP), which was repeated after at least 6 weeks of randomized monotherapy with either venlafaxine or bupropion, while controls received only a baseline LP. RESULTS: Patients (n = 9) receiving venlafaxine showed a significant decrease (42%) in their CSF 5-HIAA concentrations after treatment, but no change in other CSF measures. In contrast, patients receiving bupropion (n = 8) showed no change in CSF measures compared to pretreatment values. CONCLUSIONS: While the mechanism for this differential effect of venlafaxine remains to be determined, the current study provides confirmation of the different aminergic effects of venlafaxine and bupropion.

Adult↗
PubMed1998

Sensitization and kindling phenomena in mood, anxiety, and obsessive-compulsive disorders: the role of serotonergic mechanisms in illness progression.

A number of untreated or inadequately treated psychiatric illnesses often demonstrate syndrome progression manifested by either increasing frequency, severity, or spontaneity of episodes. Behavioral sensitization to psychomotor stimulants (and its cross sensitization to stress) and electrophysiological kindling provide two very different models for conceptualizing physiological and behavioral abnormalities that progress in severity in response to the same inducing stimulation over time. These models are highly indirect, and the behaviors induced and specific pharmacologic interventions do not directly parallel those in many of these psychiatric syndromes. Nonetheless, these preclinical models help us conceptualize potential mechanisms involved in syndrome progression based on experience-dependent modifications of the genome at the level of transcriptional regulation. In both preclinical models, agents that are effective in the earlier developmental phase of sensitization or kindling are not necessarily effective in amelioration of the full-blown syndromes, and vice versa. Thus these models also suggest a variety of intervention principles that can be directly tested in the clinic, such as differential efficacy of treatment as a function of stage of evolution of the given syndrome. Although serotonergic mechanisms do not appear central to the basic phenomena of sensitization and kindling, they appear capable of modulating their development and severity. As such, it becomes of considerable importance to assess whether serotonergic mechanisms that have been implicated in acute treatment of mood and anxiety syndromes are also involved in the longitudinal course and prevention of syndrome progression or occurrence. Identification of the more precise molecular mechanisms involved might provide a target for new therapeutic approaches to these recurrent and potentially disabling major psychiatric illnesses.

Affect↗
PubMed1998

Statistical approaches to trial durations in episodic affective illness.

In light of the high variability in illness characteristics and patterns among patients with bipolar illness, parallel group designs present severe methodologic difficulties. Crossover, off-on-off-on (B-A-B-A), and other individualized designs may be a useful substitute, but no consensus exists about how to estimate the individual trial durations required in these instances. Several methods for determining optimum trial lengths in crossover designs are presented, illustrated, and discussed. These include: chi-square (chi2) for the expected versus observed number of either episodes or days well; exceeding two standard deviations for average duration of episodes or euthymic intervals; or the Sequential Probability Ratio Test (SPRT), which detects when mean values differ from prior statistical expectations. Each method was applied to three demonstration cases using data from actual clinical trials of three patients with different patterns of recurrent affective illness. Each method detected changes in illness severity, although different tests appeared to be sensitive to differing cycle patterns in the patients illustrated. We suggest that these types of analyses and others can be used as indicator statistics to augment global impressions and clinical judgment, and to assist in determining individualized trial durations, both in formal clinical trials and in clinical treatment settings. Once individual responsivity is confirmed with an appropriate interplay of trial design and statistical analysis, the percentage response in a given population can then be compared to other agents or in other populations. Moreover, meta-analytic techniques based on addition of z scores from individuals' effect sizes can then be used to assess overall significance of a drug effect in a given population or subpopulation. The need for further development of appropriate and alternate study designs and analysis methods for bipolar illness is highlighted. Approaches to estimating required trial durations in individuals with different cycle frequencies in crossover and B-A-B-A designs constitute one element of that exploration.

Acute Disease↗
PubMed1998

Relationships between thyroid hormone and antidepressant responses to total sleep deprivation in mood disorder patients.

BACKGROUND: Acute transient antidepressant effects of sleep deprivation are consistently observed in 50% of depressed patients, but the mechanisms of these, at times, dramatic improvements in mood have not been adequately elucidated. Some, but not all, studies suggest a relationship to increased thyroid-stimulating hormone (TSH) secretion. METHODS: TSH and other thyroid indices were measured at 8:00 AM after a baseline night's sleep and at 8:00 AM following a night of total sleep deprivation (S.D.) in 34 medication-free, affective disorder patients assessed with Hamilton, Beck, and Bunney-Hamburg depression ratings as well as two hourly self-ratings on a visual analog scale. RESULTS: Compared with baseline, S.D. induced highly significant increases in TSH, levothyroxine, free levothyroxine, and triiodothyronine. The 12 S.D. responders tended to have greater TSH increases than the 15 nonresponders (p < .10). The change in Beck depression ratings significantly correlated with the change in TSH (r = -.40, p = .0496, n = 24). CONCLUSIONS: These data are consistent with several other reports of a significant relationship between degree of antidepressant response to S.D. and increases in TSH measured at 8:00 AM near their usual nadir. Acute removal of the sleep-related break on the hypothalamic-pituitary-thyroid axis remains a promising candidate for the mechanism of sleep deprivation-induced improvement in mood in depressed patients.

Adult↗
PubMed1998

Bidirectional synaptic plasticity in the rat basolateral amygdala: characterization of an activity-dependent switch sensitive to the presynaptic metabotropic glutamate receptor antagonist 2S-alpha-ethylglutamic acid.

This study examines forms of activity-dependent synaptic plasticity in the basolateral amygdala in vitro and demonstrates that a brief high frequency stimulus (HFS) train can induce a switch in the direction of the enduring change in synaptic strength induced by subsequent low-frequency stimulation (LFS). LFS (1 Hz, 15 min) of the external capsule (EC) induced a persistent 1.7-fold enhancement in the amplitude of synaptic potentials recorded intracellularly in basolateral amygdala neurons. The enhancement occurred gradually during the stimulation and was maintained for >30 min after termination of the stimulus train. LFS-induced enduring synaptic facilitation was not affected by the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoate (APV; 100 microM). Brief high-frequency EC stimulation (HFS; 100 Hz, 1 sec) induced APV-sensitive short-term potentiation (2.5-fold) that generally decayed within 10 min. When LFS was applied after recovery from the short-term potentiating effect of HFS (HFS/LFS), there was an initial transient (<10 min) enhancement of the synaptic response followed by persistent synaptic depression (synaptic potential amplitude reduced by 22% at 30 min). This represents the first demonstration of stimulus-dependent long-lasting synaptic depression in the amygdala. Application of the presynaptic (group II) metabotropic glutamate receptor antagonist 2S-alpha-ethylglutamic acid (EGLU; 50 microM) prevented the HFS-dependent switch from synaptic facilitation to depression. Thus, LFS in the in vitro amygdala slice can induce either enduring synaptic potentiation or depression, depending on whether a priming HFS train has been applied. This experience-dependent switch, a novel form of metaplasticity, is not dependent on NMDA receptors but may require group II metabotropic glutamate receptors. In the amygdala, experiential modification of activity-dependent long-term synaptic plasticity adds flexibility to the ways in which synaptic strength can be modified and could play a role in diverse amygdala-dependent processes, including the formation, storage, and extinction of emotional memory and the regulation of epileptogenesis.

Amygdala↗
PubMed1998

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.

Amygdala↗
PubMed1998

Clozapine in bipolar disorder: treatment implications for other atypical antipsychotics.

Traditional neuroleptics are often utilized clinically for the management of bipolar disorder. Although effective as antimanic agents, their mood stabilizing properties are less clear. Additionally, their acute clinical side effect profile and long term risk of tardive dyskinesia, particularly in mood disorder patients, portend significant liability. This review focuses on the use of atypical antipsychotics in the treatment of bipolar disorder focusing on clozapine as the prototypical agent. Although, preclinical research and clinical experience suggest that the atypical antipsychotics are distinctly different from typical antipsychotics, they themselves are heterogeneous in profiles of neuropharmacology, clinical efficacy, and tolerability. The early clinical experience of clozapine as a potential mood stabilizer suggests greater antimanic than antidepressant properties. Conversely, very preliminary clinical experience with risperidone suggests greater antidepressant than antimanic properties and some liability for triggering or exacerbating mania. Olanzapine and sertindole are under investigation in psychotic mood disorders. The foregoing agents and future drugs with atypical neuroleptic properties should come to play an increasingly important role, compared to the older classical neuroleptics, in the acute and long term management of bipolar disorder.

Antidepressive Agents↗
PubMed1998

Olanzapine in treatment-resistant bipolar disorder.

BACKGROUND: We evaluated the response to olanzapine in 14 consecutive patients with bipolar I disorder who were inadequately responsive to standard psychotropic agents. METHODS: Fourteen patients with bipolar I disorder by DSM-IV criteria experiencing persistent affective symptoms inadequately responsive to at least one standard mood stabilizer were treated with open-label olanzapine by one of the authors. Response was assessed with the Clinical Global Impression Scale modified for use in bipolar disorder (CGI-BP). RESULTS: The 14 patients received olanzapine at a mean (SD dosage of 14.1+/-7.2 (range 5-30) mg/day for a mean+/-SD of 101.4+/-56.3 (range 30-217) days of treatment. Of the 14 patients, 8 (57%) displayed much or very much overall improvement in their illness. In general, olanzapine was well tolerated. The most common side effects were sedation, tremor, dry mouth, and appetite stimulation with weight gain. LIMITATIONS: Data were obtained nonblindly and without a randomized control group, and olanzapine was added to ongoing psychotropic regimens. CONCLUSION: Olanzapine may have antimanic and mood-stabilizing effects in some patients with bipolar disorder, and is generally well tolerated. Controlled studies of olanzapine in bipolar disorder appear warranted.

Antipsychotic Agents↗
PubMed1998

Apoptosis of hippocampal neurons after amygdala kindled seizures.

Seizure-induced neuronal damage may involve both excitotoxic and apoptotic (programmed cell death) mechanisms. In the present study, we used an amygdala kindled seizure model to study whether apoptotic cell death occurs. To evaluate apoptosis, we counted the numbers of cells that had DNA fragments labeled at the 3' end with digoxigenin using terminal transferase (ApopTag, Oncor). Additionally, the expression of Bax and Bcl-2, two genes associated with apoptotic cell death, was also measured following kindled seizures. We found that the number of ApopTag-positive cells in the hippocampus increased 30.4% after one kindled seizure and 82.5% after 20 seizures compared to sham controls. The ApopTag-labeled cells could be mainly interneurons of the hippocampal formation, although additional studies are required. Preferential vulnerability of inhibitory interneurons is consistent with previous studies on seizure-induced cell loss. These results, coupled with our findings that the ratio of Bax/Bcl-2 expression is increased in the hippocampus by seizures, suggest that apoptosis of hippocampal interneurons may lead to dysinhibition in the hippocampus and increased seizure susceptibility.

Amygdala↗
PubMed1998

Beyond lithium in the treatment of bipolar illness.

Dramatic changes have recently occurred in the availability of treatment options for bipolar illness. Second generation mood stabilizing anticonvulsants carbamazepine and valproate are now widely used as alternatives or adjuncts to lithium. High potency benzodiazepines are also used as alternatives to typical neuroleptics, and now atypical neuroleptics are demonstrating efficacy and better side-effects profiles than the typicals. Thyroid augmentation strategies and dihydropyridine L-type calcium channel blockers require further clinical trials to define their role. Putative third generation mood stabilizing anticonvulsants lamotrigine, gabapentin, and topiramate have unique mechanisms of action and deserve further systematic study, as does the potential role for nonconvulsive brain stimulation with repeated transcranial magnetic stimulation (rTMS). These and a host of other potential treatment options now require a new generation of clinical trials to help identify clinical and biological markers of response and optimal use alone and in complex combination therapeutic regimens.

Antimanic Agents↗
PubMed1998

Attenuation of kindling-induced decreases in NT-3 mRNA by thyroid hormone depletion.

The expression of neurotrophins is altered by amygdala kindled seizures. Because thyroid hormone can regulate the transcription of neurotrophins, we asked whether thyroid hormone regulates neurotrophin mRNA expression following amygdala kindling. Rats with electrodes implanted in the basolateral nucleus of the amygdala were either depleted of thyroid hormone or given excess thyroid hormone. The rats were then kindled daily until they had one generalized seizure. The brains were removed 4 h after the seizure and processed for in situ hybridization of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) mRNAs. In non-kindled rats, thyroid hormone depletion increased the levels of BDNF mRNA in the paraventricular nucleus of the hypothalamus and the pituitary gland. NGF and NT-3 mRNA expression was not altered. In addition, thyroid hormone manipulations had no effect on kindling or on kindling-induced BDNF and NGF mRNA. However, the kindling-induced decrease in NT-3 mRNA expression in the dentate gyrus granule cell layer was significantly attenuated by thyroid hormone depletion. These effects were reversed by thyroid hormone replacement. The results indicate that thyroid hormone plays a modulatory role in the seizure-induced changes of NT-3 mRNA expression found in the dentate gyrus.

Animals↗
PubMed1998

Neural plasticity and emotional memory.

Posttraumatic stress disorder is the pathological replay of emotional memory formed in response to painful, life-threatening, or horrifying events. In contrast, depression is often precipitated by more social context-related stressors. New data suggest that different types of life experiences can differentially impact biochemistry, physiology, anatomy, and behavior at the level of changes in gene expression. Repeated separation of neonatal rat pups from their mother results in many long-lasting alterations in biology and behavior paralleling that in depression, including hypercortisolism. The role of the amygdala in modulating emotional memory is highlighted, as well as some of its unique properties such as metaplasticity (i.e., the differential direction of long-term adaptation, either potentiation or depression) in response to the same input as a function of the prior history of stimulation. The implications of these emerging data on the physiological and molecular mechanisms underlying emotional memory emphasize the particular importance of prevention and early intervention.

Amygdala↗
PubMed1998

Nimodipine monotherapy and carbamazepine augmentation in patients with refractory recurrent affective illness.

Of 30 patients with treatment-refractory affective illness, 10 showed a moderate to marked response to blind nimodipine monotherapy compared with placebo on the Clinical Global Impressions Scale. Fourteen inadequately responsive patients (3 unipolar [UP], 11 bipolar [BP]) were treated with the blind addition of carbamazepine. Carbamazepine augmentation of nimodipine converted four (29%) of the partial responders to more robust responders. Patients who showed an excellent response to the nimodipine-carbamazepine combination included individual patients with patterns of rapid cycling, ultradian cycling, UP recurrent brief depression, and one with BP type II depression. When verapamil was blindly substituted for nimodipine, two BP patients failed to maintain improvement but responded again to nimodipine and remained well with a blind transition to another dihydropyridine L-type calcium channel blocker (CCB), isradipine. Mechanistic implications of the response to the dihydropyridine L-type CCB nimodipine alone and in combination with carbamazepine are discussed.

Adult↗
PubMed1998

Gabapentin does not alter single-dose lithium pharmacokinetics.

Lithium (Li) and gabapentin are both exclusively eliminated by renal excretion. When used in combination, a competitive drug-drug interaction could possibly alter Li renal excretion with important clinical implications considering the rather narrow therapeutic index of Li. This study examined the single-dose pharmacokinetic profiles of Li in 13 patients receiving placebo and then steady-state gabapentin (mean daily dose: 3,646.15 mg). During both phases, a single 600-mg dose of Li was orally administered with serial Li levels obtained at time zero and at 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, and 72 hours. The pharmacokinetic parameters assessed were the following: area under the concentration time curve (AUC) for Li, maximal concentration of Li (Li Cmax), and time to reach peak Li concentration (Li Tmax). For patients receiving gabapentin, the mean Li AUC at 72 hours was 9.91+/-3.54 mmol x hr/mL and did not differ significantly from the mean Li AUC of 10.19+/-2.89 mmol x hr/mL for patients receiving placebo. The mean Li Cmax was 0.69+/-0.13 mmol/L for gabapentin patients and did not differ from the mean Li Cmax of 0.72+/-0.15 mmol/L for placebo patients. The mean serum Li Tmax was 1.38+/-0.62 hours for gabapentin patients and did not differ significantly from the mean serum Li Tmax of 1.5+/-0.91 hours for placebo patients. These data indicate that gabapentin treatment at this high therapeutic dose does not cause clinically significant alterations in short-term Li pharmacokinetics in patients with normal renal function. These preliminary data warrant further controlled study in a larger, more heterogenous patient sample and a longer duration of assessment, but they do suggest that these two medications may be administered in combination for the management of bipolar disorder.

Acetates↗
PubMed1998

A history of the use of anticonvulsants as mood stabilizers in the last two decades of the 20th century.

Anticonvulsants have moved into an important position as alternatives and adjuncts to lithium carbonate in the treatment of bipolar illness. Work with the nonhomologous model of kindled seizures helped in the choice of carbamazepine as a potential mood stabilizer and in the study of the mechanisms of action of the second generation anticonvulsants carbamazepine and valproate, as well as the putative third generation psychotropic anticonvulsants lamotrigine and gabapentin. Anticonvulsant neuropeptides such as TRH and nonconvulsant approaches with repeated transcranial magnetic stimulation (rTMS) also appear promising.

Anticonvulsants↗
PubMed1998

Kindling: separate vs. shared mechanisms in affective disorders and epilepsy.

Kindling is discussed in relation to affective illness as a nonhomologous model, which shares the feature of increasing illness severity and evolution over time following repeated exposures to certain forms of stimulation. This progressive aspect of kindling has proven useful in the study of approaches to pharmacotherapeutics, mechanisms and characteristics of drug tolerance, and, most recently, illness suppression through physiological rather than pharmacological strategies. Each of these themes is described and the mechanisms that have been uncovered using the kindling model are discussed in relation to how similar principles might apply in affective illness or epilepsy. It is hoped that some of the lessons from the kindling model will provide useful and novel insights into aspects of treatment and mechanisms of psychiatric and neurologic illnesses.

Amygdala↗
PubMed1998

Abnormal facial emotion recognition in depression: serial testing in an ultra-rapid-cycling patient.

Normal subjects use the right insula and bilateral anterior temporal and prefrontal cortices to recognize the emotion expressed in a human face. Mood disorder subjects have a selective deficit in recognizing human facial emotion. Brain imaging studies show that they fail to activate the right insula to the same degree as controls, even when accurately assessing facial emotion. Many issues remain, however, including whether the facial emotion recognition errors in mood disorder subjects are state dependent or persist during normal mood states (and, thus, reflect a trait abnormality). To probe this issue, we repeatedly studied a male bipolar II patient's ability to recognize faces' emotional content. This patient made significantly more errors in facial emotion recognition during the depressed state. He also demonstrated a significant negative bias when he was depressed compared with nondepressed states. This case study demonstrates the state dependency of the defect in human facial emotion recognition.

Adult↗