cyclic-gmp and Bipolar-Disorder

Bipolar manic-depressive illness is a chronic disease in which patients experience recurrent episodes of mania and depression. Patients often change from a nonverbal, retarded depression of many months' duration to a hyperactive, psychotic, manic condition during the switch. The time required for the switch from depression into mania varies from 5 minutes to a couple of days. Just before it happens, pateints experience marked insomnia and decreased rapid eye movement sleep. It is hypothesized that specific changes in brain monoamine metabolism precede the switch. Alterations in neurotransmitter metabolites, as measured in urine and cerebrospinal fluid, may precede and accompany it. The switch into mania can be precipitated by environmental stresses or by drugs that act by increasing functional brain monoamines. Drugs that reverse the manic state all share the common property of affecting biogenic amines. The switch into mania is viewed in the context of a longitudinal cyclic process and may be further studied with specific pharmacologic agents that block drug-induced maniclike states in man.

Topics: Amphetamines; Animals; Bipolar Disorder; Calcium; Cyclic AMP; Cyclic GMP; Electroencephalography; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Lithium; Methoxyhydroxyphenylglycol; Methyltyrosines; Monoamine Oxidase Inhibitors; Neurotransmitter Agents; Norepinephrine; Periodicity; Sleep

Bipolar disorder (BD) is associated with elevated cardiovascular mortality rates. We investigated the modulation of l-arginine-nitric oxide (NO) signaling in platelets from patients with BD at different phases.. Platelets obtained from 28 patients with BD and 10 healthy volunteers were analyzed for l-arginine transport, NO synthase (NOS) activity, cyclic guanosine monophosphate content, and biomarkers of oxidative stress. Expressions of NOS isoforms, soluble guanylyl cyclase, and arginase were also measured in platelets. Amino acid and C-reactive protein levels in plasma were assessed.. Plasma concentrations of l-arginine (mean [M] ± standard error of the mean [SEM] = 97 ± 10 versus 121 ± 10 µM) and its transport into platelets (median [interquartile range] = 26.0 [28.6] versus 26.5 [43.9] pmol/10(9) cells per minute) did not differ between patients with BD and controls (p > .05). Patients with BD showed reduced NOS activity (M ± SEM = 0.037 ± 0.003 versus 0.135 ± 0.022 pmol/10(8) cells, p < .001), but not endothelial NOS, inducible NOS, and arginase expression, compared with controls (p > .05). Cyclic guanosine monophosphate content was reduced (M ± SEM = 0.022 ± 0.003 versus 0.086 ± 0.020 pmol/10(8) cells, p < .05) despite the absence of changes in soluble guanylyl cyclase expression (median [interquartile range] = 21.6 [15.5] versus 9.5 [9.4] arbitrary units, p > .05) in patients with BD. Superoxide dismutase activity, but not catalase activity, was increased in patients with BD in the manic phase (M ± SEM = 2094 ± 335 versus 172 ± 17 U/mg protein, p < .001). C-reactive protein was elevated only in manic episodes (M ± SEM = 0.8 ± 0.2 versus 0.1 ± 0.02 mg/L, p < .001).. Impaired NO generation from platelets, inflammation, and oxidative stress may play pivotal roles in the multifaceted process of cardiovascular events in BD.

Topics: Adult; Arginase; Arginine; Bipolar Disorder; Blood Platelets; C-Reactive Protein; Cardiovascular Diseases; Case-Control Studies; Comorbidity; Cyclic GMP; Female; Humans; Inflammation; Male; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Signal Transduction; Superoxide Dismutase

Concentrations of cAMP and cGMP in plasma were measured in 20 drug-free melancholic patients during a simulated electroconvulsive treatment (SECT) and a bilateral ECT session. Blood samples were taken every 15 min beginning 15 min before and ending 60 min after the SECT or the ECT. Two-way ANOVA and paired t-test demonstrated a significant and greater fall in cAMP over time following SECT. ECT induced a marginal increase (P less than 0.05) at 45 min postictally. It is postulated that ECT causes an increase in cAMP levels which is masked by the decrease observed during SECT, caused presumably by the anaesthetic medication. The plasma cGMP levels were increased gradually and significantly after SECT and the same rise was observed during ECT. These effects are discussed in relation to changes in adrenergic-cholinergic activities induced by the medication and the electrical stimulus.

Topics: Adult; Bipolar Disorder; Cyclic AMP; Cyclic GMP; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales

Topics: Adult; Affective Disorders, Psychotic; Aged; Bipolar Disorder; Carbamazepine; Cyclic AMP; Cyclic GMP; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Mood Disorders

Although numerous studies have suggested that depression may be associated with a reduction in synaptic noradrenaline in the brain, direct beta-adrenergic receptor agonists have not been tested in the treatment of depression until recently. Moreover, newer theories of antidepressant action suggest that a reduction in beta-adrenergic receptor sensitivity is a better correlate of antidepressant treatment than noradrenaline turnover changes. It is possible to evaluate the beta-adrenergic receptor-adenylate cyclase complex in the human periphery by measuring the plasma cyclic AMP rise after adrenergic agonists. A clinical trial of the beta-2 adrenergic agonist salbutamol in depression provided an opportunity to test whether adrenergic receptor subsensitivity does occur during clinical antidepressant treatment. Plasma cyclic AMP before treatment with salbutamol rose 26% in response to salbutamol 0.25 mg iv. After 1 and 3 weeks of oral salbutamol treatment, depression scores declined significantly in 11 depressed patients, while the plasma cyclic AMP response to iv salbutamol declined over 60%. The beta-adrenergic adenylate cyclase remained subsensitive 4 days after cessation of salbutamol therapy. The results support the concept that receptor sensitivity changes occur during human antidepressant therapy. Data are presented that Li, too, markedly reduces activity of beta-adrenergic adenylate cyclase in humans. The effect was evaluated by studying the effect of Li at therapeutic serum concentrations on the plasma cyclic AMP response to subcutaneous epinephrine. The Li effect is specific, since the plasma cyclic AMP response to glucagon is not inhibited. The plasma cyclic GMP response to subcutaneous epinephrine, suggested as a model for presynaptic alpha-noradrenergic mechanisms, is also partially inhibited by Li therapy. Since cyclic AMP and cyclic GMP may be viewed as balancing substances, their interaction may provide a mechanism for Li's dual clinical effects in mania and depression. It is important that in vivo techniques be developed for evaluating receptor changes. The plasma cyclic AMP response to adrenergic stimulation provides an in vivo measure of receptor function that can be useful in studying drug effects during the clinical treatment of humans.

Topics: Adenylyl Cyclases; Albuterol; Bipolar Disorder; Cyclic AMP; Cyclic GMP; Depressive Disorder; Epinephrine; Humans; Lithium; Norepinephrine; Receptors, Adrenergic; Receptors, Adrenergic, beta

Lithium-treated and drug-free individuals were each given 0.5 mg epinephrine subcutaneously and blood samples withdrawn for measurement of plasma cyclic AMP and cyclic GMP. The rise in plasma cyclic GMP in response to epinephrine was found to be partially inhibited by lithium treatment, and previous reports of lithium inhibition of the plasma cyclic AMP rise were replicated. Effects of lithium on cyclic AMP and cyclic GMP may relate to lithium's biphasic efficacy in depression and mania.

Topics: Adult; Bipolar Disorder; Cyclic AMP; Cyclic GMP; Epinephrine; Female; Humans; Lithium; Male; Middle Aged

Human CSF cyclic nucleotides do not distinguish manic-depresive patients or schizophrenic patients from controls, although a "high CSF cyclic AMP" subgroup of poor-prognosis schizophrenics is still under investigation. Neuroleptic therapy raises CSF cyclic GMP and lowers CSF cyclic AMP, at least in the responder subgroup of a clinically heterogeneous patient population when neuroleptics that are good adenylate cyclase inhibitors in vitro are used in the treatment. This is consistent with the concept that neuroleptic treatment in humans involves blockade of dopamine neurotransmission. Attempts to correlate the decline in CSF cyclic AMP concentration with clinical improvement may be important. Lithium treatment does not alter the level of CSF cyclic AMP, which probably derives largely from dopamine-related neurotransmission that lithium does not affect. However, the plasma cyclic AMP response to epinephrine is inhibited by lithium at therapeutic doses in vivo after chronic treatment. The lithium effect is somewhat specific in that the glucagon-stimulated rise in plasma cyclic AMP is not affected. The results in clinical experiments support the theory that norepinephrine-sensitive adenylate cyclase inhibition in brain is involved in lithium action. Research to attempt to distinguish lithium-responsive from lithium nonresponsive patients on the basis of sensitivity to lithium inhibition of the epinephrine-induced rise in plasma cyclic AMP is of considerable potential practical importance.

Topics: Adolescent; Adult; Bipolar Disorder; Cyclic AMP; Cyclic GMP; Female; Glucagon; Humans; Lithium; Male; Middle Aged; Propranolol; Regression Analysis; Remission, Spontaneous; Schizophrenia

Topics: Adult; Bipolar Disorder; Cyclic GMP; Depression; Female; Guanylate Cyclase; Humans; Lithium; Male; Physostigmine