Lithium carbonate and brain function. I. Cerebral-evoked potentials, EEG, and symptom changes during lithium carbonate treatment.

Eighteen patients were studied with behavioral ratings and the somatosensory (SER), auditory (AER), and visual (VER) cerebral-evoked response and quantified EEG before and during lithium carbonate treatment. The amplitude of early positive SER components and most AER components increased during treatment, but VER did not change. The intensity of EEG delta and theta frequencies increased, and the dominant alpha frequency slowed. Before treatment, there were few significant correlations to symptom intensity. Patients with an increase in symptoms on treatment had the greatest increase in EEG delta intensity and the dominant alpha frequency slowed in patients who became more depressed. The EEG slowing in patients with a normal sensorium and the change in cerebral cortical activity after transmission in the somatosensory pathway over just three synapses demonstrate a unique and specific effect of lithium carbonate on brain function.

Alpha 2-adrenergic and opiate receptor blockade. Synergistic effects on anxiety in healthy subjects.

To evaluate interactions between the opiate and adrenergic systems in healthy humans, concomitant administration of the opiate antagonist, naloxone hydrochloride, and the alpha 2-adrenergic receptor antagonist, yohimbine hydrochloride, was compared with the administration of placebo and of each drug separately. A synergistic effect of the combination (larger than the sum of the effects of the two drugs separately) was observed on subject ratings of nervousness, anxiety, tremors, palpitations, nausea, hot and cold flashes, and increased plasma cortisol concentrations. In addition, following the combination, each of the male subjects studied reported a full penile erection lasting at least 60 minutes, an effect not reported when each drug was given separately. These results demonstrate that interactions between the opiate the adrenergic systems have important implications for our understanding of the cause and treatment of anxiety disorders and male impotence.

Abnormal regulation of noradrenergic function in panic disorders. Effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder.

Clonidine hydrochloride, an alpha 2-adrenergic receptor agonist that decreases noradrenergic function, was administered to 21 healthy subjects and 26 drug-free patients with agoraphobia and panic attacks. Clonidine produced significantly greater decreases in plasma MHPG levels and sitting and standing diastolic blood pressure and significantly smaller increases in growth hormone levels and self-rated drowsiness in the patients. These findings indicate that the regulation of noradrenergic activity is aberrant in some patients with panic disorder, since a previous study demonstrated that patients with panic disorder exhibit increased plasma MHPG levels, blood pressure, and behavioral responses to the alpha 2-adrenergic receptor antagonist yohimbine. The increased dynamic range of noradrenergic activity observed as an increased sensitivity to both clonidine and yohimbine may reflect abnormalities in the regulatory inputs to noradrenergic neurons, or dysfunction in the alpha 2-adrenergic receptor effector coupling mechanism or the intracellular effector system.

Noradrenergic function and the mechanism of action of antianxiety treatment. I. The effect of long-term alprazolam treatment.

There is preclinical and clinical evidence suggesting that one neural mechanism responsible for antipanic efficacy is a reduction in brain noradrenergic function. Alprazolam, a triazolobenzodiazepine, has been demonstrated to have antipanic properties; however, to our knowledge, its effects on noradrenergic function have not been established. To assess whether alprazolam alters noradrenergic function, the effects of alprazolam on baseline plasma free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), and yohimbine-induced increases in plasma MHPG level, anxiety-nervousness, blood pressure, and somatic symptoms were studied in 14 patients with agoraphobia and panic disorder. Long-term alprazolam treatment significantly reduced plasma MHPG baseline and blunted the yohimbine-induced increases in plasma MHPG, anxiety-nervousness, and sitting systolic blood pressure. These observations suggest that the antipanic mechanism of action of alprazolam may be due in part to an interaction between benzodiazepine-sensitive and noradrenergic neural systems.

Noradrenergic function and the mechanism of action of antianxiety treatment. II. The effect of long-term imipramine treatment.

Considerable preclinical and clinical evidence indicates that increased noradrenergic function is involved in the development of anxiety. Imipramine hydrochloride, which has complex effects on noradrenergic function in animals, is effective in patients with agoraphobia and panic disorder. To assess the effects of imipramine on noradrenergic function in patients, plasma levels of free 3-methoxy-4-hydroxyphenylglycol (MHPG) and yohimbine-induced increases in plasma MHPG levels, anxiety-nervousness, blood pressure, and somatic symptoms were studied before and during long-term imipramine treatment in 11 patients meeting DSM-III criteria for agoraphobia with panic attacks. Long-term imipramine treatment significantly decreased baseline plasma MHPG levels by 38% and modestly potentiated yohimbine-induced increases in blood pressure, but it did not alter yohimbine-induced increases in plasma MHPG levels or in patient ratings of anxiety-nervousness. The therapeutic effects of imipramine in panic disorder may relate more to the decrease in norepinephrine turnover than to alterations of alpha 2-adrenergic autoreceptor function.

Serotonin function in panic disorders. The effect of intravenous tryptophan in healthy subjects and patients with panic disorder before and during alprazolam treatment.

Preclinical evidence suggests that alterations in serotonin function may relate to the development of anxiety and the therapeutic effectiveness of antianxiety treatments. Serotonin increases prolactin release, and intravenous administration of the serotonin precursor, tryptophan, produces reliable elevations in serum prolactin levels. To evaluate serotonergic function, the effects of intravenous tryptophan on prolactin secretion were determined in 23 drug-free patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder and 21 age- and sex-matched healthy subjects. In nine of the patients the tryptophan infusion was repeated during long-term alprazolam treatment. The ability of tryptophan to increase prolactin levels was not different between the patients and healthy subjects and was not altered by alprazolam treatment. These findings suggest serotonin function may be normal in panic anxiety disorders and the antipanic mechanism of action of alprazolam may be unrelated to effects on serotonin activity.

Alterations in cerebral laterality during acute psychotic illness.

A dichotic listening test was used to assess cerebral laterality in 26 right-handed patients with schizophrenic, schizoaffective, or primary major depressive illness and in 23 controls. Clinical state was assessed by twice-daily nurses' ratings and patient self-ratings. Ratings of psychotic thought and behavior were lower during the week of highest laterality than during the week of lowest laterality (P less than .01). Similarly, when most improved, patients had higher laterality than when most ill (P less than .01). Changes in laterality were not specific to diagnostic group, were not present in control subjects, could not be related to direct drug effects, and were independent of changes in accuracy of performance. There were large, stable, interindividual differences in degree of lateralization, but no differences between patients and controls. These results are consistent with the hypothesis that in acute psychotic illness there is a breakdown in the interhemisphere inhibition that normally mediates cerebral laterality.

Noradrenergic function in panic anxiety. Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder.

Yohimbine, an alpha 2-adrenergic receptor antagonist that increases noradrenergic function, was administered to 20 healthy subjects and 39 drug-free patients with agoraphobia and panic attacks. Following drug administration, changes in plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), BP, pulse rate, and subjective ratings of feelings and somatic symptoms were examined during a four-hour period. Yohimbine produced significantly greater increases in patient-rated anxiety, nervousness, palpitations, hot and cold flashes, restlessness, tremors, piloerection, and sitting systolic BP in the total patient group compared with healthy subjects. There were significant correlations between the yohimbine-induced rise in plasma MHPG level and patient-rated anxiety and nervousness and the frequency of reported panic attacks. Patients experiencing frequent panic attacks (greater than 2.5 per week) had a significantly greater plasma MHPG response to yohimbine than the healthy subjects and patients having less frequent panic attacks. These observations support a hypothesis of increased sensitivity to augmented noradrenergic function in anxiety states associated with panic, and they suggest that impaired presynaptic noradrenergic neuronal regulation may exist in patients with frequent panic attacks.

Major depression in patients with agoraphobia and panic disorder.

A review of the life-time occurrence of major depression, the temporal relationship of major depression to episodes of panic and agoraphobic disorders, and the severity of anxiety and depressive symptoms were determined in 60 patients with agoraphobia or panic disorder. Forty-one (68%) of the patients had a past or current episode of major depression, and 35 (85%) of these patients had endogenous-type major depression. Twenty patients (33%) had an episode of primary major depression, and an average of three years separated the end of primary major depression and the first panic attack. Secondary major depression occurred in 28 patients. Patients with a history of major depression had a more severe anxiety disorder. These data support the view that in a subgroup of patients, episodes of depression and panic anxiety disorder may be manifestations of a common underlying pathogenic process.

Agoraphobia with panic attacks. Development, diagnostic stability, and course of illness.

A structured psychiatric interview was used to examine the symptom history of 55 patients meeting DSM-III criteria for agoraphobia with panic attacks and five patients meeting DSM-III criteria for panic disorder. Anticipatory anxiety and generalized anxiety occurred in over 80% of the patients, and these anxiety states together with panic attacks and phobic avoidances had courses that were chronic and unremitting. Major depression occurred in 70% of the patients and had an episodic course that differentiated it from the anxiety states. Other frequently reported disorders were childhood separation disorder (18%), alcoholism (17%), and obsessive compulsive disorder (17%). An initial nonspontaneous first panic attack and separation anxiety was associated with earlier onset and longer duration of agoraphobia and panic disorder. An inaccurate cognitive appraisal of the initial panic attack frequently led to the rapid development of subsequent agoraphobia. Caffeine consumption exacerbated anxiety in 54% of the patients and triggered panic attacks in 17%. Fifty-one percent of female agoraphobics experienced premenstrual exacerbation of anxiety symptoms.

Desipramine-yohimbine combination treatment of refractory depression. Implications for the beta-adrenergic receptor hypothesis of antidepressant action.

Preclinical investigations have shown that combined administration of the alpha 2-adrenergic receptor antagonist yohimbine hydrochloride and the tricyclic antidepressant desipramine hydrochloride produces a reduction in brain beta-adrenergic receptor function within four days. Since the ability of antidepressant treatments to reduce beta-adrenergic receptor function has been hypothesized to mediate antidepressant efficacy, it was predicted that combined desipramine-yohimbine treatment would be a more rapid-acting and potent antidepressant regimen than desipramine alone. In the present investigation, the effects of desipramine (N = 11) and desipramine-yohimbine (N = 10) treatment on depressive symptoms, norepinephrine turnover, and blood pressure were determined in patients with major depression who had a history of nonresponse to standard antidepressant treatments. Neither desipramine nor desipramine-yohimbine proved to be an effective treatment, although concomitant yohimbine administration did attenuate the ability of desipramine to decrease plasma free and 24-hour urinary 3-methoxy-4-hydroxyphenyl-ethyleneglycol levels and blood pressure. Fifteen of the 21 patients eventually had a good response to pharmacologic treatments, particularly a desipramine-lithium carbonate or lithium carbonate-tranylcypromine sulfate combination treatment (11 of 14 responded). This study provides evidence against the beta-adrenergic receptor hypothesis of antidepressant action.

Increased anxiogenic effects of caffeine in panic disorders.

The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages.

Noradrenergic function in schizophrenia.

Yohimbine, an alpha 2-adrenergic receptor antagonist that increases noradrenergic function, was administered to 16 healthy subjects and 18 drug-free schizophrenic patients with (n = 10) and without (n = 8) tardive dyskinesia (TD). Outcome measures of this double-blind, placebo-controlled study included changes in behavior, plasma 3-methoxy-4-hydroxy-phenylglycol (MHPG) level, blood pressure, and heart rate. A subgroup of six patients experienced a notable dysphoric arousal reaction that occurred 60 to 90 minutes following administration of 20 mg of yohimbine, this reaction was not observed in healthy subjects. The schizophrenic group as a whole (not the subgroup) showed a statistical trend toward a greater yohimbine-induced increase in plasma MHPG level and systolic sitting blood pressure. The patients with TD did not differ from those without TD or from healthy controls in their response to yohimbine. These results do not support the hypothesis that noradrenergic dysfunction plays a strong central role in the pathogenesis of schizophrenia or TD. However, further studies of noradrenergic dysfunction in sub-groups of patients with schizophrenia are indicated.

alpha 2-Adrenergic receptor sensitivity in depression. The plasma MHPG, behavioral, and cardiovascular responses to yohimbine.

alpha 2-Adrenergic receptors play a major role in the regulation of the noradrenergic system. To assess the function of these receptors relative to possible abnormalities in noradrenergic function in depression, responses to the alpha 2-antagonist yohimbine hydrochloride were investigated in 45 depressed patients and 20 healthy control subjects. Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), blood pressure (BP), pulse, subjective mood, and somatic symptoms were measured before and during yohimbine and placebo administration. The 25% increase in plasma MHPG levels produced by yohimbine did not differ between patients and controls. Mood responses also tended to be similar between groups, with patients reporting only minor improvement in depression following yohimbine. However, yohimbine caused significantly greater increases in somatic symptoms and tended to produce a greater increase in BP in patients than in controls. Evaluation of patient subgroups divided by the presence or absence of melancholia, psychosis, prominent anxiety, or personality disorder did not demonstrate consistent differences. In contrast, comparison of these findings with a prior study showed that patients with panic disorder and agoraphobia who received yohimbine manifested significantly greater increases in MHPG levels and ratings of anxiety, nervousness, and depression than depressed patients. These findings suggest that patients with major depression do not demonstrate marked abnormalities in alpha 2-adrenergic autoreceptor function.

Serotonin function and mechanism of action of antidepressant treatment. Effects of amitriptyline and desipramine.

The effects of amitriptyline hydrochloride and desipramine hydrochloride treatment on brain serotonin (5-HT) function were investigated in 21 patients. The ability of an intravenous infusion of the serotonin precursor tryptophan to raise serum prolactin (PRL) levels was determined in 13 depressed patients during placebo administration and after 28 to 35 days of treatment with either amitriptyline or desipramine. Both desipramine (N = 7) and amitriptyline (N = 6) significantly increased the PRL rise induced by tryptophan compared with a preceding placebo period. In contrast, following long-term amitriptyline and desipramine treatment, the ability of tryptophan to increase PRL was enhanced two weeks following abrupt cessation of amitriptyline therapy (N = 5), but not after discontinuation of desipramine therapy. The results of this investigation are consistent with electrophysiologic and behavioral studies in laboratory rats and suggest that desipramine- and amitriptyline-induced alterations in 5-HT function may be related to their antidepressant mechanism of action.

Serotonergic function in depression. Prolactin response to intravenous tryptophan in depressed patients and healthy subjects.

There is considerable evidence that serotonergic function may be reduced in the brains of depressed patients. Serotonin is an effective stimulant of prolactin release, and intravenous (IV) tryptophan (the amino acid precursor of serotonin), when administered to healthy subjects, produces a reliable and robust increase in serum prolactin level. To evaluate serotonergic function in depressed patients, we gave 25 patients and 19 age- and sex-matched controls tryptophan, 7 g IV. There was a marked blunting of the maximal prolactin response to the tryptophan in both the male and female patients. The patient control differences could not be accounted for on the basis of age, sex, or time without medications. The data provide strong support for a possible serotonergic abnormality in depression.

A molecular and cellular theory of depression.

Recent studies have begun to characterize the actions of stress and antidepressant treatments beyond the neurotransmitter and receptor level. This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3',5'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3',5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stress-vulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.

State anxiety, physical activity, and urinary 3-methoxy-4-hydroxyphenethylene glycol excretion.

Measurement of urinary 3-methoxy-4-hydroxyphenethylene glycol (MHPG) levels has been suggested as possibly being important in elucidating the role of central noradrenergic function in affective illnesses. The influence on urinary MHPG excretion of the state variables of physical activity and stress has not been clearly defined in previous studies. During a baseline medication-free period, 24 hospitalized depressed female patients underwent a five-day protocol including an eight-hour period of either enhanced or restricted activity. Throughout the protocol, independent measurements of telemetered mobility and stale anxiety were obtained. There were no significant effects of physical activity on urinary MHPG levels. Furthermore, baseline urinary MHPG levels and baseline state anxiety did not covary significantly. However, within-individual analyses yielded a highly significant relationship between changes in urinary MHPG levels and changes in state anxiety. The data suggested that those patients with lower baseline MHPG levels were those more prone to experience increased anxiety under environmentally "activating" circumstances.

Primary affective disorder, clinical state change, and MHPG excretion: a longitudinal study.

Urinary 3-methoxy-4-hydroxyphenethylene glycol (MHPG) excretion, which is thought to reflect CNS norepinephrine metabolism, has been shown to be significantly decreased in some depressed patients. Although there is consensus that urinary MHPG excretion varies directly with mood in rapidly cycling bipolar patients, there is little information on longer term state changes, such as those that accompany recovery from depression. Ten female patients with diagnoses of primary affective disorder were studied initially during an inpatient hospitalization and restudied at least ten months after discharge. Five healthy female comparison subjects were also studied over a similar interval of time. During the baseline period, the patient sample excreted less MHPG than did the comparison group. Improvement in clinical state from a seriously depressed baseline was associated with a significant increase in MHPG excretion, while the patients with recurrences of depression showed no change and continued to excrete less MHPG than the comparison subjects. These results suggest that urinary MHPG excretion may represent an index of psychobiological state in depressive patients.

Receptor sensitivity and the mechanism of action of antidepressant treatment. Implications for the etiology and therapy of depression.

Considerable evidence suggests that the acute effects of antidepressant treatments on brain norepinephrine (NE) and serotonin (5-HT) systems cannot account fully for their delayed therapeutic action. This review evaluates the effects of long-term antidepressant treatment on biogenic amine metabolism and on various indexes of presynaptic and postsynaptic receptor function. In contrast to variable effects on NE and 5-HT turnover and on presynaptic receptor sensitivity almost all long-term antidepressant treatments produce consistent alterations in a number of measures of postsynaptic amine receptor sensitivity. Long-term treatment has been found to reduce beta-adrenergic sensitivity while enhancing responses to serotonergic and alpha-adrenergic stimulation, suggesting that modulation of receptor sensitivity may be a mechanism of action common to tricyclic antidepressants, "atypical" antidepressants, monoamine oxidase inhibitors, and electroconvulsive therapy. These findings provide support for hypotheses of amine receptor abnormalities in depression and indicate the need for expanded studies of amine receptor function in patients.