Bipolar disorder is a mental health condition caused by malfunctioning neurotransmitters in the brain.

The consequence of this malfunctioning is a shifting to extreme moods. With bipolar disorder, formerly called manic depression, the shift is usually not sudden but slowly becomes more extreme. Bipolar disorder is a severe condition that sometimes requires hospitalization. Four different forms of the disorder exist but Bipolar I is considered the most serious. 1. Manic Episode
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A person diagnosed with Bipolar I must have had at least one manic episode in his lifetime. A manic episode is marked by lack of sleep, feelings of superiority, extreme talkativeness, and extreme risk-taking behaviors such as spending all of his money or sleeping with strangers. Depressive Episode

A Bipolar I diagnosis does not require a history of depressive episodes, which are very similar in nature to unipolar depression. Most patients do have depressive episodes. In fact, these episodes are often wrongly diagnosed. Impairment

With either type of extreme mood episode, the condition must be severe enough to interfere with daily activities. Risk of Suicide

The rate of suicide attempts among patients with bipolar disorder is 20 times higher than for the general population. People who have bipolar disorder are more likely to attempt suicide as they are emerging from a depressive episode. Risk of Violence

Manic episodes can compromise cognitive ability and can prevent rational thought. As a result, people in the midst of a manic episode have a greater risk of attempting violence against another person.

Read more: Pathophysiology of Bipolar I eHow.com http://www.ehow.com/facts_4798154_pathophysiology-bipolardisorder.html#ixzz1LlJU5r00

Disorder

Bipolar Disorder What happens in the brain? The two main neuroanatomic circuits involved in mood regulation are:
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the limbic-thalamic-cortical circuit the limbic-striatal-pallidal-cortical circuit.

]A dysfunction in any brain region associated with these mood-regulating circuits may lead to the development of a mood disorder. However, it is not certain whether a disturbance to these areas of the brain causes the onset of mood disorders or whether they are affected during the course of the disease. It is possible that abnormalities in these circuits confers a biological vulnerability, which when combined with environmental factors causes mood disorders (Soares & Mann, 1997). The main brain areas involved in bipolar disorder include thefrontal and temporal lobes of the forebrain , the prefrontal cortex , the basal ganglia and parts of the limbic system . The hippocampus may also play a role in bipolar disorder, as structural changes to this area of the brain have been associated with the disorder in some individuals. The cerebral cortex is involved in thought processes and it is possible that abnormalities in this part of the forebrain are responsible for the negative thoughts that are associated with the depressive episodes of bipolar disorder. Structural imaging studies have recently demonstrated a neuroanatomical basis to bipolar disorder (Manji & Lenox, 2000). Although the findings are not as consistent as those reported for schizophrenia, they have demonstrated a reduction in overall brain volume. Specifically, an enlargement of the third and lateral ventricles and a reduction in the volume of grey matter in parts of the medial and orbital prefrontal cortices,ventral striatum and mesoisotemporal cortex. The metabolic rate and blood flow to these areas are also disrupted indepression. The reduced brain volume is partly due to a reduction in the number of neurons and glial cells in layers II and III in the forebrain of depressed patients. These two layers have been demonstrated to be important in bipolar disorder (Manji & Lenox, 2000).

Biochemistry neurotransmitters are involved in the aetiology of mood disorders, especially the monoamines (noradrenaline,serotonin and dopamine) and acetylcholine. While earlier simplistic theories suggested that an excess of neurotransmitters occured during a manic episode and a decrease occurred during depression, this is clearly not the case. Instead, it is the effectiveness of the cell functioning under the modification and control of neurotransmitters that underlies the pathoetiology of mood disorders. The Cholinergic System Lower than normal levels of choline have been found in the erythrocytes of bipolar patients prompting researchers to believe that an imbalance between cholinergic and catecholaminergic activity is important in the pathophysiology of bipolar disorder. Further evidence implicating the cholinergic system in bipolar disorder is the antimanic properties of cholinergic agonists and the modulation of manic symptoms by the cholinesterase inhibitor phygostigmine (Manji & Lenox, 2000; MullerOerlinghausen et al, 2002). The Monoamine System The monoamine hypothesis of depression states that depression is caused by depleted levels of the monoamines,noradrenaline, serotonin and/or dopamine, in the central nervous system (Schildkraut, 1965). While this simplistic model is known not to provide an understanding of the pathoetiology of mood disorders, it continues to have value in providing patients with an explanation of the biochemical basis of mood dysregulation. Studies report that plasma noradrenaline is reduced to normal resting output in bipolar depressed patients (Manji & Lenox, 2000). In patients with the increased concentrations of noradrenaline and the noradrenaline metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), in the urinary and cerebrospinal fluid suggests that noradrenaline and MPHG output is higher in mania than in depression and there may be higher values in unipolar versus bipolar depression (Manji & Lenox, 2000). Research also reports that an altered sensitivity of the E2- andF2adrenergic receptors may play a role in the aetiology of mood disorders, possibly through enhanced E2autoreceptor activity leading to a decrease in noradrenaline release (Delgado, 2000; Manji & Lenox, 2000). The density and affinity of E2receptors have also been shown to be increased in the hypothalamus

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,amygdala , hippocampus and cerebellum (Delgado, 2000).

of depressed suicide victims

Substantial evidence for the role of serotonin in patients with bipolar disorder comes from the study of serotonin receptors. Several studies have shown an increase in the density of serotonin 2 receptors in the platelets and brain of depression patients. This increase may be due to an adaptive up-regulation in response to decreased synaptic serotonin. Adecrease in the density of serotonin 1A receptors has also been found in several areas of the brain in depressed patients, especially those with bipolar disorder (Delgado, 2000; Manji & Lenox, 2000). Studies on serotonin and serotonin metabolism have shown a reduced concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA) in bipolar disorder patients, especially in aggressive patients and those who have attempted suicide. Tryptophan is an essential amino acid on which serotonin synthesis is dependent. Prescribing tryptophan to patients with depression may occasionally result in the reversal of the therapeutic effect of selective serotonin re-uptake inhibitor administration and initiate the recurrence of depression. Finally, genetic studies have been designed to investigate the association between bipolar disorder and polymorphisms in the serotonin transporter and tryptophan hydrolase, important molecules involved in the key steps of serotonin metabolism (Delgado, 2000; Manji & Lenox, 2000). One of the most convincing rationale for the role of dopamine in bipolar disorder is the vital role dopamine plays in the reward and/or incentive motivational circuitry. In fact, loss of motivation is one of the key features of depression. The most consistent biochemical finding in depression is the reduced concentration of homovanillic acid (HVA), a major dopamine metabolite, in the cerebrospinal fluid (Manji & Lenox, 2000). A function for dopamine in the aetiology of bipolar disorder is suggested by the role that dopamine agonists have in precipitating mania. It has been postulated that dopamine abnormalities are involved in the hyperactivity associated with the severe stages of mania; whereas noradrenaline is associated with hypomania as observed in bipolar II disorder (Manji & Lenox, 2000). The Hypothalmic-pituitary-adrenal Axis (HPA Axis) The hpa axis consists of a feedback loop that includes the hypothalamus, pituitary and adrenal glands. The hormones that regulate the HPA axis are corticotropin releasing hormone(CRH), argenine vasopressin (AVP),

adrenocorticotropin hormone(ACTH) and cortisol. The HPA axis is involved in thestress response and abnormalities in the HPA axis have long been implicated in mood disorders. Increased HPA axis activity has been associated with mixed-maniac states, depression and classic manic episodes (Manji & Lenox, 2000; Varghese & Sherwood Brown, 1999). Substance P (SP) SP is a neuropeptide found widely distributed throughout the central and peripheral nervous systems. It colocalises with serotonin in the nuclei raphes, with dopamine in the mid-brain and striatum, and with GABA and acetylcholine in the cortex. It has important neuromodulatory effects. For example, SP regulates the release of acetylcholine in the cortex. There are several observations that suggest SP may be involved in the aetiology of the mood disorders; such as, SP containing neurons are found in the areas of the brain implicated in the aetiology of mood disorders, including the locus ceruleus and the limbic system. Studies with rats have also shown that chronic application of tricyclic antidepressants causes a downregulation of SP in the limbic system. One recent study has even shown that the NK1 receptor antagonists the NK-1 receptor is the receptor for SP have an antidepressant and anxiolytic activity. However, further research is required before the role of SP in mood disorders is fully elucidated and the possible therapeutic benefits discovered (Lieb et al, 2002). Signalling System Dysfunction Studies to date have failed to identify a common action of antidepressants at the level of the monoamines and their receptors. An emerging hypothesis suggests that antidepressants modify a pathway that occurs following monoamine release and receptor binding (Duman et al, 1997). Following neurotransmitter release and binding at the post-synaptic membrane, a secondary messenger signalling cascade occurs that ultimately elicits the cellular response. This is an extremely complex pathway and dysfunction in these second messenger mechanisms have been implicated in the pathoetiology bipolar disorder. Some agents involved in these responses include cyclic AMP, protein kinases and phosphoinositol. Cyclic AMP and Protein Kinase A There is evidence of an altered post-receptor sensitivity of the cyclic AMP (cAMP) generating system in mood disorders, while the number of receptors themselves remains unaltered. Investigation into the cAMP/protein kinase A (PKA) system found that concentrations of the PKA regulatory subunits in

the cytoplasm are significantly lower in cells of the frontal, temporal, occipital and parietal cortex, cerebellum and thalamus of bipolar disorder patients. Studies have also shown a higher concentration of the cAMP stimulated phosphorylation of Rap1, a protein found in the platelets of bipolar patients (Manji & Lenox, 2000). The phosphorylation of Rap1 is related to intracellular calcium signalling pathways. Abnormalities in calcium signalling have been implicated in bipolar disorder; findings show elevated intracellular calcium concentrations in the platelets, lymphocytes and neutrophils of bipolar disorder patients. Calcium is very important in most intracellular signalling pathways, and in the regulation of neurotransmitter synthesis and release. Elucidation of abnormalities in these pathways could be beneficial in the treatment of bipolar disorder (Manji & Lenox, 2000). Neurotrophic Factors Sustained activation of the cAMP system in certain regions of the brain occurs in patients treated with antidepressants. This leads to increased expression of the transcription factor cAMP response element bindingprotein (CREB), which causes increased expression of certain brain-derived neurotrophic factors in neurons of the hippocampus and cerebral cortex. Specific neurotrophic factors are vital for the survival and functioning of particular neurons. These observations have led to a new hypothesis, the molecular and cellular theory of depression. The molecular and cellular theory of depression suggests that atrophy of hippocampal neurons and a decrease in these survival promoting neurotrophic factors may be involved in depression. Recent clinical imaging studies have supported this by demonstrating a decreased volume of certain brain structure in the brains of patients with depression. This theory also suggests that, via secondary messenger signalling systems, antidepressants increase the concentration of neurotrophic factors which are essential for neuronal survival (Duman et al, 1997; Duman, 2002). Phosphoinositol and Protein Kinase C Several studies of bipolar patients have shown abnormalities in the phosphoinositol/protein kinase C (PKC) signalling system. One such study has demonstrated significantly higher concentrations of 4,5-bisphosphate (PIP2) in the platelet membranes of patients in the manic phase of bipolar disorder; they also found that the levels of PIP2 increased when cycling from the euthymic state into the manic state. Additionally, the activity of platelet

PKC was found to be elevated in patients during a manic episode of bipolar disorder (Manji & Lenox, 2000). G-proteins Several independent studies have shown increased concentrations of the stimulatory subunit (GEs) of G-protein E in the brains of bipolar disorder patients, specifically in the frontal, temporal and occipital cortices. Other studies have suggested there is also increased presence/activity of Gproteins in the leukocytes of untreated manic patients and the mononuclear leukocytes of bipolar, but not unipolar, patients. Currently, there is no evidence to indicate that the increased concentration of GEs are caused by gene mutations; it has been suggested that they could be caused by a change in any one of the biochemical pathways leading to the transcription and translation of the GEs gene (Manji & Lenox, 2000). Genetic Factors There is a well recognised genetic component to the aetiology of bipolar disorder; multiple family studies have shown that there is higher prevalence of bipolar disease in family members of patients with bipolar disorder, compared with psychiatrically healthy controls (Alda , 1997). The lifetime risk of bipolar disorder in first-degree relatives of a patient with bipolar disorder is 4070% for a monozygotic twin and 510% for all other firstdegree relatives (Muller-Oerlinghausen et al, 2002). There is some evidence to suggest that bipolar I and II disorders are genetically distinct subtypes. However, the rapid cycling form of bipolar disorder does not appear to be genetically different from the non-rapid cycling form (Alda, 1997). Research suggests that the inheritance pattern of bipolar disorder is complex and non-mendelian. In bipolar disorder the interactions of multiple genes and non-genetic factors confer vulnerability, with genomic imprinting, mitochondrial inheritance, environmental and development factors all playing a part (Muller-Oerlinghausen et al, 2002; NIMH, 2000). Several hypotheses have been proposed for the nature of genetic transmission of bipolar disorder, including the X chromosome-dominant mode of inheritance and the continuum hypothesis of Goldin et al, 1983, but none of them have been consistently supported (Alda, 1997). Molecular genetic studies have revealed potentially relevant gene loci for bipolar disorder: 18p11, 18q22, 4p16, 21q21 and Xq26. However, no specific genes have been identified as candidate genes for bipolar disorder. This is partly due to the difficulty in distinguishing this disorder from other psychiatric disorders, resulting in heterogeneous sampling populations.

Candidate genes may include the genes for the serotonin transporter and receptors, the dopaminergic receptors, monoamine oxidase-A, catechol-Omethyltransferase, the phospholipase C-K1 isozyme and the hormone proenkephalin (Alda, 1997; Muller-Oerlinghausen et al, 2002). PATHOPHYSIOLOGY The etiology of BD remains ill-defined, though it now is known that it may arise from a complex interaction of genetic predisposition, neurochemical influence, anatomical variation, substance abuse, and stressful perinatal and childhood experiences (for example, verbal, physical and sexual abuse).1921Although the exact gene or genes and mode of transmissi3on remain illusive, BDs inheritability is demonstrated by the fact that if one parent has BD, there is a 25 percent chance that any of his or her children will have BD or major depressive disorder, and if both parents have BD there is a 50 to 75 percent that their children will have a mood disorder. Concordance rates for BD are 70 percent in monozygotic twins and 15 percent in dizygotic twins.22 Neurochemical abnormalities have been implicated as contributing to the development of BD. Specifically, a paucity of the "inhibitory" neuro-transmitter -aminobutyric acid, or GABA, and elevated levels of the neurotransmitters norepinephrine and dopamine at the synapses between neurons in the brains limbic systemwhich regulates mood and emotionshave been implicated as facilitating the excessive transmission of neuronal impulses resulting in a manic episode.23 Meanwhile, inadequate levels of the neurotransmitters serotonin, norepinephrine and dopamine have been identified as hindering neuronal transmission resulting in a depressive episode.24 Neuroimaging studies support this model by demonstrating abnormalities in blood flow and glucose metabolism in limbic system structures and in the amygdalathe area of the brain known to be involved in processing emotions.2529 MEDICAL MANAGEMENT An acute manic episode often constitutes a medical emergency and usually is treated in a hospital. Initially, high doses of a mood stabilizer such as lithium, valproate sodium or carbamazepine are prescribed; the latter two also are anticonvulsant medications. In addition to a mood stabilizer, an antipsychotic medication (risperidone, olanzapine or quetiapine) and a highpotency benzodiazepine (lorazepam or clonazepam) often are prescribed to attain a degree of control of acute agitation.30,31 People who cannot tolerate the medication may be given electroconvulsive therapy, or ECT.32 Once the agitation is controlled, the antipsychotic medication and the benzodiazepine usually are discontinued. The dosage of lithium, valproate sodium, carbamazepine or a combination of these medications then is adjusted to obtain long-term mood stabilization and to prevent recurrence of both mania and depression. During this maintenance phase of treatment because of a less-thanoptimal response, approximately 50 percent of patients also take an antidepressant (most commonly a selective serotonin reuptake inhibitor, or SSRI, or bupropion), 40 percent take a benzodiazepine, and 30 percent take an antipsychotic agent.33,34 Psychosocial interventions such as behavioral, cognitive and interpersonal therapy also are offered at this time and appear to augment the effects of the medications and forestall recurrence.35 Risperidone, olanzapine and quetiapine are classified as second-generation antipsychotic medications. These medications are used to decrease agitation, control psychotic symptoms and promote mood stabilization. They derive their antimanic effect by blocking dopamine neural transmission and their antidepressive effects by enhancing serotonin and norepinephrine neural

transmission.3639 The occurrence of extrapyramidal movement disorders is considerably less frequent than with first-generation antipsychotic medications such as chlorpromazine. However, when extrapyramidal movement disorders do arise, they often have an orofacial component such as acute dystonia creating mastication muscle spasms, pseudoparkinsonism resulting in a masklike face and drooling, and tardive dyskinesia manifesting as lip smacking and tongue protrusion. Occasionally, the use of these medications also is associated with the development of hypotension, orthostatic hypotension, weight gain, tachycardia, anticholinergic effects and sexual dysfunction. Lorazepam and clonazepam may help control acute agitation, hyperactivity and insomnia by enhancing the activity of GABAa major inhibitor of the norepinephrine and serotonin neurotransmitter systems in the central nervous system, or CNS. Occasionally, the use of these medications is associated with respiratory depression and hypotension. The mood-stabilizing agent lithium may derive its antimanic effect from its ability to inhibit the release of the CNS neurotransmitters norepinephrine and dopamine from nerve terminals and synapses, and its antidepressant effect may be derived from its ability to increase CNS serotonin levels.40 In some people, lithium may cause nausea, tremor, cognitive impairment and hypothyroidism, which may lead to a goitera diffuse, nontender, enlarged thyroid glandand weight gain. Approximately 30 percent of patients who take lithium develop electrocardiogram changes, the most common of which are bradycardia and a benign, reversible reduction in the amplitude of T waves.41 Nephrotoxicity also may develop as evidenced by polyuria and polydipsia. Valproate sodium and its enteric-coated divalproex formulation also is a mood-stabilizing agent. Its actions on inhibitory and excitatory amino acid systems and membrane-associated ion channels in the brain may be responsible for its stabilizing effect.42 Long-term use is associated with approximately 9 percent of patients developing leukopenia, 7 percent developing thrombocytopenia and a lesser percentage having a decrease in fibrinogen concentration.43,44 Carbamazepines mood-stabilizing effect also is believed to be derived from its ability to stabilize sodium and potassium channels and the upregulation of GABAB receptors.45 Like valproate sodium, long-term use of carbamazepine is associated with decreased white blood cell and platelet counts. SSRIs such as fluoxetine exert their antidepressant effect by preventing presynaptic neurons from reabsorbing serotonin from the synaptic cleft (the space between two neurons) for recycling. Thus, the concentration of serotonin in the cleft is heightened, and neuronal activity is enhanced. Use of the majority of SSRIs frequently is associated with diarrhea, nausea, dizziness, insomnia, tremor, headache, sexual dysfunction (for example, decreased libido, ejaculatory dysfunction, erectile dysfunction and anorgasmia) and occasionally an increase in bleeding time.46,47 Bupropion, an atypical antidepressant, exerts its effects by preventing the reuptake of norepinephrine and dopamine from the synaptic cleft, thereby facilitating neural transmission.48 SSRIs and bupropion are used much more frequently than the tricyclic antidepressant medications, as they are less likely to cause a switch to mania.49 ECT is indicated for patients who have manic episodes with severe agitation or severe depressive episodes that do not respond to medication.49 The electrical currents used in ECT create massive

neuronal electrical discharges in the CNS that result in a seizure. It is postulated that after a number of treatments, appropriate neuronal activity is restored.50 ECT usually is given two to three times a week for several weeks until the patient improves. Approximately 90 percent of patients enter a remission within one to two weeks, which usually is quicker than for patients who take medications. Some psychiatrists recommend a dental examination for their patients before ECT to determine if the anesthesiologist needs to adjust the procedure because of dentures or problem teeth.51 Positioning the electrodes farther away from the masseter muscles is associated with decreased dental injuries.52 Psychosocial treatment provided as an adjunct to medication appears to decrease the likelihood and severity of recurrent episodes and improve the patients quality of life. Initiated during or shortly after an acute manic or depressive episode, the therapeutical protocol encourages adhering to the drug regimen, educating the patient and family about the illness (for example, being able to recognize early signs of relapse) and offering practical techniques for coping with stressors such as loss of an important relationship or changes in work, school or home life.53