Bipolar Disorder

Aetiology

What happens in the brain?

The two main neuroanatomic circuits involved in mood regulation are:

• 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 the frontal 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 in depression. 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; Muller-Oerlinghausen 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 mania 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 a₂- and b₂adrenergic receptors may play a role in the aetiology of mood disorders, possibly through enhanced a₂-autoreceptor activity leading to a decrease in noradrenaline release (Delgado, 2000; Manji & Lenox, 2000). The density and affinity of a₂-receptors have also been shown to be increased in the hypothalamus , amygdala , hippocampus and cerebellum  of depressed suicide victims (Delgado, 2000).

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. A decrease 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 (5-HIAA) 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 the stress 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 NK-1 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 binding-protein’ (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 (Ga_s) of G-protein a 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 G-proteins 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 Ga_s 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 Ga_s 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 40–70% for a monozygotic twin and 5–10% for all other first-degree 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-O-methyltransferase, the phospholipase C-g1 isozyme and the hormone proenkephalin (Alda, 1997; Muller-Oerlinghausen et al, 2002).