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Bipolar Disorder: Roles of neurotransmitters and signal transduction

This systematic review provides a critical insight into the biochemical aetiology of bipolar disorder. It presents an overview of the findings collected from various researches which investigate the abnormalities in neurotransmitter systems and signal transduction system. The results confirm hypothesises established in earlier theories of the causes of Bipolar disorder form pharmacological investigations. However these results are correlation, culmination of these variables and others such as environmental and genetics may influence the development of bipolar disorder. Aims, Evaluation, implications and limitations of these studies are included in this review.

Bipolar disorder also known as manic depressive disorder can have a negative effect on an individuals’ mood, relationships, and everyday life. This disorder can affect the cognitive functions and is known to impair cognitive areas such as attention, executive functions, learning, memory and psychomotor speed. Bipolar usually develops in late teens or early adulthood but can sometimes develop early on in childhood. Symptoms usually build up later on in life. The disorder can lead to poor school performance, damaged social lives and jobs. . It affects both sexes equally in all age groups and approximately 3–5% of the general population are affected (Baldessanni, 2002). Bipolar disorder is the most rigorous forms of all mental illness and is characterized by swinging moods .The clinical course of illness can vary from a mild depression to a rigorous form of mania. The condition has a high rate of recurrence and can lead to suicide if left untreated (15% of patients) this is most likely to occur during a depressive state.

Bipolar disorder is a severely debilitating brain affective disorder which has had very little extensive research conducted on; in particular the biochemistry component of the disorder has had relatively few research studies compared to genetics. Due to its high rate of suicide and reoccurrence rate it is essential to develop effective treatment to prevent the two main problems of bipolar disorder (Shastry, Burker S, 2005). The manifestations of the symptoms are often mistaken for unipolar depression (31%) and therefore misdiagnosis of bipolar often occurs (Berk et al, 2006).

Research into the neuropathological aspect paves the way for more future developments in viable treatments, which should be more tolerable for patients for this affective mood disorder, this could include improving existing drug treatments.

Although Bipolar is one of the oldest known mental illness it was never classified; the symptoms were described and examined throughout history and sometimes the etiologies which were established were imprudent. Mania was seen as occurring from an excess of yellow bile, or a mixture of black and yellow bile. The theory of a link between mania and depression goes back to the 2nd century AD. Soranus of Ephedrus (98-177 AD) described mania and depression as diseases with different etiologies; however, he acknowledged that “many others consider melancholia a form of the disease of mania”. Depression was formally known as melancholia. In 1650, a scientist named Richard Burton determined the characteristics of depression in ‘The Anatomy of Melancholia’. His findings are still used today in the mental health field, and he is established as being the father of the study of depression.Emil Kraepelin (1856-1926), a German psychiatrist first termed the disease as ‘manic depressive psychosis’. He studied the disorder in untreated patients. In 1948, Dr. Cade a psychiatrist found out that Lithium Carbonate could be used as a successful treatment of manic depressive disorder. This was the first time a drug had been discovered that proved to be a successful treatment of this condition. The current term bipolar disorder replaced manic depressive disorder in 1980, and featured as diagnostic term in the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-III).Most diagnosis of bipolar disorder are based on DSM IV (2000).

Due to the complexity of brain function, the aetiology and pathophysiology of the disorder is not very well understood .The debate as to whether it is genetic factors or neurobiological factors which contribute to bipolar disorder is ongoing. Genetics have been known to play a major role in aetiology of bipolar disorder from early on, however many theories suggest neurotransmitter dysfunctions in depression, and therefore maybe the best explanation to finding the cause of Bipolar disorder would be to investigate a chemical basis of the disorder, as this review will examine. The pathophsysiolgy has recently been overtaking research on genetics of bipolar disorder. It would be essential to study the same neurotransmitters which have implicated in cause of depression and the areas affected by medications which alleviate symptoms of manic-depression (Ackenheil, 2001).

Theories about neurotransmitter abnormalities in bipolar disorder have been created by experiments which have been created by experiments studying the effects of pharmacological treatments. Lithium was first used 40 years ago to treat bipolar disorder, studies on the effects of lithium, its target and mechanism of action on bipolar patients have indicated mostly monoamine neurotransmitter abnormalities are involved behind bipolar disorder however even though large amounts of research on neurotransmitter abnormalities have been conducted the aetiology of bipolar is far from completely understood. Many patient are unaffected by lithium, this shows that bipolar disorder may have more than one cause maybe this accounts for the various symptoms involved in this disorder.

Many models focus on one neurotransmitter or neurotransmitter system as the case of bipolar disorder however these models cannot be sufficient enough to explain the array of symptoms. A valid general theory has to consider opposite effects of activity of neurons leading to the cycle of mood states, this could be a system involving the releases of transmitters, abnormality in cerebral activities or a regulatory protein involved in the interaction of various systems on levels of signal transduction.

The debate above provides the basis for this review. To understand the neurochemistry of bipolar disorder the molecular and cellular systems have to be determined. This literature review is organized around the signal transduction pathways and central neurotransmitter systems and convergence of these areas to provide an insight into the pathophysiology of bipolar disorder. Neurotransmitters involved in this review are serotonin, dopamine and noradrenalin.

The neuroamine exert their action through postsynaptic receptors which are coupled to Guanine nucleotide binding proteins (G proteins). This is the main part of the intracellular signalling mentioned in this review. Other systems which have also been studied are sodium and calcium transport, disturbances in these systems have been implicated in the physiology of bipolar disorder, although this topic is beyond the scope of this review and there is relatively little research compared to G coupled proteins and cyclic AMP system, Given this, and the authors own personal interests, it was decided to focus on G coupled proteins and cyclic AMP system and the other main pathway phosphoinositide.

3. Aims

This literature review aims to provide a critical evaluation of the research investigating the structures and circuits involved in the aetiology of bipolar affective disorder. Initially neurotransmitters and signal transduction will be examined and outlined by introducing the most popular and widely-used theories associated with the development of bipolar disorder and explain by what is meant by ‘bipolar’. Following this a search protocol is included: an explanation of how the reviewed articles were sourced and analysed. After which will follow a comprehensive review of the studies found in the search about how each neurotransmitter and signal transduction affect bipolar disorder. Also the disagreements and contradictions in the literature will be discussed. The implications and limitations of these findings of the studies found will then be considered and topics for future research presented.

4. Bipolar Affective Disorder

4.1. Diagnostic Criteria

There are two types of bipolar disorder; Bipolar I and Bipolar II. Bipolar II consist of symptoms which are not as severe or prolonged as Bipolar I. The criteria for bipolar disorder is complex and is separated into six criteria sets theses are: single manic episode, most recent episode hypomania, most recent episode depressed, most recent episode mixed, most recent episode depressed and most recent episode unspecified.

The table below summarizes the main DSM-IV classification (4th edition) criteria for the diagnosis of bipolar I and bipolar II disorder.

Table 1

DSM-IV category

Criteria

Bipolar I

Presence of one or more manic or mixed episodes, current or most recent episode: accompanied by one or more depressive episodes .Severe: with psychotic features

In partial or full remission:

With catatonic features

With postpartum onset

Current or most recent major depressive episode: significant distress occurs.

Depressive state occurs more frequently then mania.

Bipolar II

No history of manic episode, not as severe as Bipolar I. Characterised by at least one hypomanic episode and depressive episode

4.2. Major depression

Depression can distort an individual’s way of thinking about themselves, their lives and of other people around them. Individuals who are diagnosed with depression tend to have higher negative views and fail to see the positive in any situation. Depression can also occur as anger. If episodes of low or depressed mood and a decrease in energy, activity, interest, or pleasure occur for two weeks the individual is diagnosed as major depressive ( DSM IV, 2000)

4.3. Mania

Mania is the abnormal elevation of emotions, usually occurrence of irritable mood, inflated self esteem and may feature delusions or hallucinations (psychotic symptoms) when symptoms are less severe the patient is experiencing a hypomania episode. Mania can manifest itself in many forms. The DSM-IV splits the severity of mania symptoms into further subgroup for accurate diagnosis:

Mild: symptoms barely meet criteria for an episode of mania.

Moderate: There is a high increase in either activity level or impaired judgment.

Severe without psychotic features: The patient requires continuous supervision to prevent physical harm to self or to others.

Severe with psychotic features: The patient has delusions or hallucinations which may be mood-congruent or mood-incongruent.

The table below summarises the symptoms of mania and depression

Table 2

Mania

Depression

Need for sleep is decreased

Increased talkativeness, pressure to keep talking, hyperactiveness

Flight of ideas may be erratic- raving thoughts

Incomprehensible speech

Excess involvement in pleasurable activities e.g. impulsive sex- potential for painful consequence

Having unrealistic beliefs in abilities

Increasingly involved in goal relative activities, starting new projects

Feeling constantly tired

Having problems concentrating, remembering, and making decisions

Lack of pleasure in activities

Negative thoughts

Being restless or irritable

Changing eating, sleeping, or other habits (excess sleep usually occurs)

Contemplating death or suicide, or attempting suicide.

An individual with hypomanic episodes may have increased energy although the symptoms are not as severe as typical mania, the symptoms may come in episodes that last less than a week, do not require hospitalisation and will not be classified as full blown bipolar disorder I. A person having a hypo manic episode may feel they are on a high, be extremely productive, and function well. The individual may not perceive their behaviour as abnormal although these mood swings may be apparent to friends and family members. Without treatment, however, individuals with hypomania may develop severe mania or depression.

4.4. Definition issues

Very few patients with bipolar alternate between episodes with ‘pure’ mania or ‘pure’ depression, many however have a variety of patterns and are regularly in a mixed state and rapid cycling between mania and depression occurs. Some experience months of depression followed by months of mania, some can swing states in a matter of hours (Berk et al 2005) this is usually defined as ‘bipolar spectrum’ and can complicate diagnosis. There are unclear boundaries which can limit the selection of appropriate treatment. Accurate diagnosis on basis of clinical interviews may not be possible as many patients at the time of interview are in one phase. The psychotic symptoms reflect the person's extreme mood. For example, if a person is having a manic episode he/she may experience psychotic symptoms such as believing he or she is famous, has a lot of money, or has special powers which may make them invincible , this can be quite dangerous and can lead to death( Bauer, Michael et al, 2002). On the other hand, a person experiencing a depressive episode may believe he or she is ruined and penniless, or has committed a crime which in turn can lead to suicide. Due to these psychotic symptoms in individuals with bipolar disorder are sometimes wrongly diagnosed as having schizophrenia, another severe mental illness that is associated with hallucinations and delusions.

People with bipolar disorder may also have other behavioural problems. Many turn to alcohol or substances, others tend to have attention deficit hyperactivity disorder (ADHD) or post traumatic stress disorder (Strakowski S.M. et al, 1998) so initially it's not easy to recognize these problems as signs of a major mental illness.

Individuals with Bipolar disorder sometimes go through states where they exhibit minimal symptoms however they still have the vulnerability for mood deregulation, this state is called euthymia (Strakowski et al.2004). There are no separate criteria for diagnosis of children although it has been stated that bipolar disorder in children is slightly different from bipolar in adults.

4.5. Treatment

The treatment for Bipolar I Disorder is usually lifelong therapy with a mood-stabilizer this can be Lithium, Carbamazepine, or Divalproex / Valproic acid often in combination with an antipsychotic medication. Many of these medications are anticonvulsants except for lithium. Anticonvulsants medications help control moods although are usually used to control seizures. An antipsychotic medication and/or a benzodiazepine medication are often added to the mood-stabilizer in mania. In depression, Quetiapine, Olanzapine, or Lamotrigine is frequently taken with the mood-stabilizer. Alternations occur between medications, in depression, the mood-stabilizer is sometimes substituted for another mood-stabilizer, or in some cases two mood-stabilizers can be used together. Occasionally, antidepressant medication is used in depression. However as antidepressant medication can trigger mania, antidepressant medication is always taken in combination with a mood-stabilizer or antipsychotic medication to prevent mania (Ackenheil, 2001).

Research has shown that the most effective treatment for bipolar disorder is a combination of supportive psychotherapy, and the use of a mood-stabilizer and antipsychotic medication (Miklowitz D.J. 2006)

5. Monoaminergic Neurotransmitter systems

5.1. Serotonergic system

Serotonin pathways originate in the raphe nuclei and project throughout the cerebral cortex. Serotonin is known to interact with the other neurotransmitters, it modulates different neuronal activities, Serotonin triggers sleep & wake cycles, mood and emotional behaviour; deficiency can lead to migraines (Birkmeyer, W. and P. Riederer, 1989) this neurotransmitter increases the threshold for pain, reduces "arousal functions," hyperactivity results in improved appetite, weight increase, an increased urge to sleep, lowered consciousness, slower thought processes, and lack of drive, most of which have been shown to be symptoms of depression in bipolar disorder.

Serotonergic cell bodies originate mainly in the upper Pons and the midbrain-specifically, the median and Dorsal raphe nuclei, the Candal locus ceruleus, the Postrema area, and the inter peduncular area. These neurons project to the basal ganglia, the limbic system, and the cerebral cortex. (Kaplan et al. 1994).

5.2. Noradrenergic system

The Noradrenalin (NA) system originates in the locus coeruleus, lateral tegmental area in the brain stem and projects diffusely through axonal pathways to the cortex, amygdale and hippocampus, in the CNS it is involved in a wide range of neurological and psychological functions, which include cognition, attention, emotion, and memory formation (Robbins and Everitt 1995, Moore and Card 1984).

Activation of NA neurons increases cellular responsiveness to sensory information as inhibition of the background activity of the target neurons occurs and also increases the selectivity of the responses to relevant stimuli (Foote et al 1983). NA is also involved in the fight or flight reaction. NA changes the efficiency of the excitatory and inhibitory synaptic transmission in particular neurons although it is dependent on the subtypes of adrenergic receptor (AR) and secondary messengers (Dohlman Et al 1991).

5.3 Dopamingenic system

There are eight major dopaminergic pathways in the brain. The three main pathways originate from the midbrain, they are as follow:

Mesolimbic pathway–consists of a bundle of dopaminergic fibres which are associated with the reward circuit. This pathway develops from the ventral tegmental area and innervates various formations of the limbic system, which include the nucleus accumbens. The mesolimbic pathway is involved in memory and is important for motivating behaviours.

Mesocortical pathway - also originates in the ventral tegmental area, although also projects to the frontal cortex and surrounding areas. Dysfunction in this pathway might be the cause of some of the symptoms such as hallucinations and disordered thinking in bipolar disorder. Medications used to reduce psychotic delirium block this pathway, and also reduce the overall activity of the frontal lobes.

Tuberoinfundibular pathway- is located in the hypothalamus and releases dopamine into the portal vessels thus regulating the functioning of the pituitary. These distributed pathways are responsible for behavioural areas such as impulsivity and attention, reward seeking, emotional processing, working memory, and other executive functions.

The actions of the neurotransmitter dopamine are usually connected through G-protein-coupled receptor slow transmission, which in turn modulates fast neurotransmission in glutaminergic and GABA- ergic neurones. There are two types of dopamine receptors D1-type and D2-type. D1-type receptors (D1 and D5) are mostly coupled to Gas and then stimulate the production of the second messenger cyclic-AMP (cAMP), whereas D2-type receptors (D2, D3, and D4 included) are coupled to Gai ⁄ o and decrease the production of cAMP and related downstream pathway. The various types of dopamine receptors are diffused throughout different areas of the brain (Greengard P. 2001)

6. Signalling transduction

6.1. G- Coupled proteins and Cyclic AMP system

G-proteins are an important component of the intracellular signalling pathway; they interlink receptors in the membrane to the different intracellular effecter molecules which in turn produces responses. G-proteins are made up of 3 sub units: an a subunit which binds and hydrolyzes guanosine triphosphate (GTP) these can be further divided into subunits of Gas, Ga, Gaq, Gao and b and g subunits which are firmly bound to one another. Various combinations of protein structures can be established out of these subunits thus creating a number of receptors for different or similar signal transduction systems. Small changes in the subunits of the G proteins can highly alter the order of events in signalling from receptors to the intracellular targets (Birnbaumer L, 1992, Spiegel et al., 1992) These G-protein coupled receptors stimulate or inhibit mainly two second messenger systems: cAMP and Phosphoinositol

After receptor activation, G-proteins connect to various effectors (enzymes). This pathway involves coupling of G protein (inhibitory or stimulatory) sub units to enzymes for example adenyl cyclase (AC). Different forms of the enzyme AC catalyze to produce cAMP this is via adenosine triphosphate (ATP).cAMP controls cellular functions such as metabolism and gene transcription.As cAMP degrades quite quickly in the brain by phosphodiesterase binding of cAMP to another enzyme cAMP-dependent protein kinase (as protein kinase A) is used as an indirect measurement of cAMP. This enzyme is critical for connecting any short term changes in neurotransmitter signalling to long term neurobiological changes (Beavo J.A, 1974, Scott JD, 1991).

6.2. Phosphoinositide (PI) Pathway

Another signalling path way involved in the coupling of neurotransmitter receptors is phosphoinositide , this pathway involves the phosphatidylinositol-specific phospholipase (PLC) enzyme, and the G-protein subtypes Gq/G11, (Perez et al ,2000)

Hydrolization of inositol-containing phospholipid phosphatidylinositol 4, 5-bisphosphate (PIP2) to two important second messengers: 1, 2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) is induced by the activation of the receptors which stimulate PLC (Smrcka et al 1991). Inositol monophosphate (IP) is made by conversion of IP3. IP is then again converted into inositol which is then available for resynthesis of PI.

Lithium decreases the level of inositol in the brain, it blocks the conversion of IP to inositol by interfering with inositol monophosphate phosphatise conversion of IP to inositol.

7. Theories

There have been a number of theories of depression and mania separately. The main neurotransmitter system implicated in the development of bipolar disorder is the serotonin system and is still the most widely studied system; however there is evidence suggesting that other neurotransmitter systems also play important roles (Barros et al. 2002). The biogenic amine theory of depression (Bunney and Davis 1965; Schildkraut 1965) is based upon a link between pharmacological alterations (medications taken by Bipolar patients) of monoamines and modulation of affective disorders. Decreasing amine neurotransmitters (noradrenalin (NA) and serotonin (5-HT) in the synaptic clefts) leads to an increased incidence of bipolar affective disorder. Another theory suggests that antidepressants alter the concentration of neurotrophic factors which are essential for neuronal survival (Duman et al, 1997; Duman, 2002). Although recently it has been suggested that instead of being a simple case of depletion in some crucial cerebral transmitter; concentrations depression may be the result of a disturbed balance between various regulatory systems, which may lead to transmitter over activity in some brain regions (Syvälahti 1994). Another hypothesis by Harro & Oreland (1996) the neurobiological aetiology of depression may lie in the alteration of the noradrenergic innervations from the locus coeruleus, which, in turn, may lead to dysfunction of serotonergic and dopaminergic neurotransmission.

Theories associated with the Multicomponent, cellular signalling pathways suggest that the interaction at various levels is important, which form complex signaling networks essentially allowing the cell to obtain, process, and respond to information (Bourne HR, Nicoll R,1993, Weng G et al, 1999). The cascades of signals are assisted by these networks in a matter of milliseconds, they are crucial for physiological processes as they can alter the strength and duration of outputs and feedback. Thus abnormalities in these pathways may have variety of affects in different neurological disorders (Bhalla U.S. 1999).

Patients treated with antidepressants have increased activation of cAMP system in particular regions of the brain. This causes the high expression rate of the transcription factors that are involved in this system (cAMP response element binding protein- CREB) which leads to the increased expression of neutrophic factors in hippocampus and cerebral cortex neurons theses neurotrophic factors are essential for survival and functioning of certain neurons these studies have lead to the ‘molecular and cellular theory of depression’.

8.Method

8.1. Search protocol

A breakdown of how the search was conducted is presented in Figure 1 below:

Less detail Level of detail in search more detail

Start Time of search finish

Keywords

Bp = Bipolar Disorder S= Serotonin D= Dopamine

N= Neurotransmitter ST= Signal Transduction NA= neuroadrelaline

GP= G proteins PI= Phosphoinositide cAMP= cAMP pathway

8.2. Selection method

Articles were searched on several journal databases these included web of knowledge, Science Direct and Medline. Key words were chosen to assist with the search. Key words included: signal transduction, neurotransmitters, bipolar disorder, mania, serotonin, dopamine, noradrenalin and depression. Articles were selected by at first by reading the abstract and deciding whether the article was directly answering or related to the review question. If this link was established, the article was considered as having passed the first stage of screening

Once all databases had been searched for those articles that passed stage one screening, further analysis was carried out. Articles weren’t excluded on basis of country of origin or date of publishing. Many studies incorporated different factors for example

8.3. Articles excluded

Certain articles which were found within the search protocol were not included in this literature review. There is a large amount of literature investigating the genetic links to neurotransmitter receptors and bipolar disorder that purely focused on this factor although articles that purely focused on this factor were not included in the review.

9. Findings

Direct and indirect methods which have been used in the studies include: brain studies, CSF studies, platelet studies and psychopharmacological have all been included in this review as it is difficult, to measure the chemical and physiological activity within the brain in vivo.

Peripheral lymphocytes share many common characteristics with neuronal cells thus considered suitable models for testing various hypothesises. Lymphocytes have various neurotransmitter receptors on their cell membrane

9.1.Neurotransmitter studies

Noradrenergic system has been shown to be involved in the pathophysiology of bipolar disorder. In depressive states, noradrenergic system has under functioned these results from these studies are taken from indirect measurements of noradrenalin metabolism in body fluids. Measuring desmthylimipramine, the growth hormone secretion shows estimate activity of noradrenergic neurons in the brain (Laakmann et al 1990).

Abnormalities in the level of noradrenalin in plasma of patients has been observed which support the hypothesis that this neurotransmitter is involved in the aetiology of bipolar disorder , in subjects with mania the concentrations of NA has been increased ( Manji, Lenox, 2000) also the metabolite of noradrenalin (-methoxy-4-hydroxyphenylglycol -MHPG) has been established to be higher concentration in the urinary and cerebrospinal fluid of mania state than in depressive state ( Goodwin et al, 1990, Bowden CC 1997, Schatzberg AF et al 1995, Manji et al 1997). These were all longitudinal studies and therefore had higher validity compared to studies only examining one state of mood in bipolar disorder. Higher values were also noted in unipolar depression compared to bipolar depression (Goodwin FR, Jamison KR 1990, Manji et al 2000).

Lower noradrenalin output and altered sensitivity of a2 receptor activity have been discovered in depressive states this has been indicated by the lowered growth hormone response to clonindine leading to a decrease in noradrenalin activity compared to in maniac state where noradrenalin release is increased (Delgado, 2000; Manji & Lenox, 2000). Increased levels of a2 receptors in the hypothalamus, amygdale, hippocampus and cerebellum have also been reported (Delgado 2000, Young et al 1994, Vawter M.P et al 2000,).

Another group of studies on serotonin and serotonin metabolism have shown that a lower concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) was found in bipolar disorder patients, particularly in aggressive bipolar patients and those who have attempted or contemplated suicide but were raised in patients with mania (Manji & Lenox, 2000, Traskman et al 1981, Swann et al 1983, Asberg et al, 1984). Smaller numbers of serotonin uptake sites were also found in post mortem brains of depressed individuals with bipolar disorder ( Leake et al, 1991) other drug studies on Tryptophan, an essential amino acid on which serotonin synthesis is dependent on have established that prescribing tryptophan to patients with depression may sometimes result in the reversal of the therapeutic effect of selective serotonin re-uptake inhibitor administration and depression may reoccur, this suggests that serotonin levels in brains of bipolar disorder patients may not be the only cause of this disorder.

Extensive results from CSF experiments, serotonin receptor and re uptake site binding studies, pharmacologic studies have been achieved which support the theory that alterations of serotonergic neurotransmission in depressive states occur (Goodwin et al 1990, Maes et al 1995, Garlow et al 1999). In studies of CSF 5-HIAA in patients with bipolar disorder in mania episode has generally produced inconsistent and conflicting results (Goodwin 1990, Shiah et al 2000). Most studies found no difference in levels of CSF 5-HIAA levels between depressed state and manic state, two reported both manic and depressive states have lowered CSF 5-HIAA levels and one reported manic have significantly lowered levels of CSF 5-HIAA compared to control subjects. More research in this area needs to be conducted in order to achieve consistent results (Goodwin, 1990). Maes et al (1995) and Garlow et al (1999) researches found decreased concentration of radioligand binding to the serotonin transporter which is involved in taking up serotonin from the synaptic cleft. These results were found both in platelets and mid brain of depressed subjects.

Positron emission tomography (PET) studies have also reported decreases in 5-hydroxytryptamine (5- HT)1A receptor binding potential in the raphe and hippocampus and amygdala of the brains of depressed patients, especially in patients with bipolar and in unipolar patients with history of bipolar in their family, indicating a genetic link ( Drevets, 1999)

To produce a more direct measurement of serotonergic system function neurotransmitter depletion models are used in the case of bipolar disorder tryptophan depletion to lower serotonin levels is used. Serotonin synthesis is dependent on Tryptophan, an essential amino acid. Depletion of tryptophan is created by the ingestion of preparations which contain high levels of other amino acids but are lacking tryptophan which then reverses the response of some antidepressants and the recurrence of depression. Although patients who take tryptophan but do not have depression and non medicated patients with depression do show signs of depression or intensification of depression (Spleiss O, 1998, Manji et al 1998). These results show that the neurobiological system is complex, other mechanisms may be more important, identifying a single cause of this disorder is quite impossible.

Levels of dopamine metabolite (HVA) in the cerebrospinal fluid of depressed bipolar patients taking medication were reported to be normal or increased compared to control groups (Gerner et al 1984, Subrahmenyam 1975, Manji et al 2000). After drug washout, the level of HVA in CSF were reduced which suggest that untreated bipolar patients are in a hypodopaminergic state. Levels of HVA are found to be increased mainly in manic state ( Gerner et al 1984, Banki et al 1981, Goodwin et al 1973, Sjostram et al 1972, Tandon et al 1988, Vestergaard 1978) and levels of urinary dopamine are also increased ( Noslow 1983). In a study by Sherl et al (2006) levels of HVA in the CSF were negatively correlated with suicide attempts in depressed bipolar patients. Dopamine is essential in the reward/motivational circuitry, these results may account for the lack of motivation in depression of bipolar disorder. However if psychosis is present in these patients, results may be affected; level of psychical activity may also affect the assessment of dopamine metabolites.

Medication which inhibit dopaminergic transmission have shown to create an anti manic action in bipolar disorder where drugs which have a stimulating effect on dopamine synthesis or activate dopamine receptors create mania (Yatham 2002; Schatzberg 2004; Silverstone and Silverstone 2004).These results account for the theory that dopamine abnormalities have a role in the hyperactivity symptom of mania (Manji & Lenox, 2000).

9.2. Signal transduction

Drug therapy studies have found that lithium decreases the function of numerous G proteins by inhibiting the cyclic AMP production, including the stimulatory sub type Gas (Mork A et al. 1992;Avissar S et al. 1988;Risby ED et al. 1991). Increased levels of G protein (except Gai , Gao, or Gb) in the frontal, temporal, and occipital cortex area of the brain were found (Young et al. 2002) these results were obtained from post-mortem studies of bipolar subjects’ brains. In the same brain samples increased G protein were correlated with the activity of adenylylcyclase (AC- the major effecter enzyme which is known to couple to Gas) this shows functional relevance these findings were replicated in other studies, using different brain tissue samples.

Other methods such as using specific binding assays for G protein can measure the levels of G protein a subunits in a sample. GTPgS binding is commonly used in these studies, an increase of G- proteins were found in the subjects’ especially in the frontal cortex region (Friedman E et al.1996) however many of these studies use a small sample and cannot represent a wider population of bipolar patients. Although a bigger sample was used in a study conducted by Dowlatshahi D et al ( 1999) using subjects from Stanley Foundation Neuropathology Consortium, no overall differences were shown in Gas levels compared to control samples although higher levels of Gas were found in subjects who had not been on lithium treatment at the time of death compared to those who had been on drug therapy this shows the aggressiveness of lithium and may contribute to the differences in results compared to earlier studies . These studies support the hypothesis of stating hyperfunctionality of G-proteins in bipolar patients by Schreiber et al (1991) an increase of cyclic AMP signalling has also been shown.

Lymphocytes and platelets experiments on G protein function of bipolar patients show an increased activity. Most of the studies show an increased activity of G-proteins connecting to hormones, neurotransmitters and electrical AMP production (Schreiber et al., 1991; Young et al., 1994; Perez et al., 1995) and to the PI system (Brown et al.1993; Friedman et al.1993).

Evidence suggesting the role of cAMP generating system has arrived from many different studies; altered receptors of the cAMP system in bipolar patients have developed sensitivity (Wang et al. 1997). Studies in the leukocytes have shown decreased function of AR in depressed patients this could be an abnormality in the AR/Gs/AC complex suggested by the various intracellular theories (Wright et al. 1984) although these studies need to be replicated in order to have a more concrete results, other confounding factors may be involved maybe environmental factors are the cause to these changes?

Reports of increased cyclic AMP signalling in bipolar disorder patients, higher forskolin- stimulated adenylate cyclise activity and increased cAMP dependant protein phosphorylation in platelets of the patients (Risby et al, 1999).

PI signalling abnormalities have been noted in several studies in peripheral cells and post mortem brain tissue samples of patients who had bipolar disorder, PFC levels of free inositol in bipolar were lower in bipolar disorder than control subjects ( Shimon et al 1997) although there no difference between bipolar patients, control and suicide victims in inositol monophosphate activity. In other studies there weren’t any differences in free inositol levels in non medicated bipolar patients (Atack et al 1995, Banks et al 1990) reduced linking of inositol to PI intracellular pools in bipolar subjects were also discovered (Atack et al 1995). Free inositol levels in the frontal cortex of post-mortem brains of bipolar patients were increased although no change was distinguished in the IMPase activity (Mori H et al 1991).

In bipolar disorder patients brain tissues the G protein coupled phosphoinositide system was shown to be impaired in the occipital cortex although not the frontal or temporal cortex (Matthews et al 1997, Jope et al 1996). However long term Lithium treatment could have a confounding effect on the results; the depletion in the inositol levels may be just starting event on the mechanism action of treatment rather than an ongoing factor in the clinical effects. Maybe the deficiency in PI signalling is a result of an adaptive increase in Gαq/11 expression. Decreased levels of Gq/11 were found in lithium treated patients compared to control subjects, no differences were found in non -medicated patients with bipolar disorder (Manji et al 1995). The amount of impairment in the system correlated with the amount of lithium concentration found in the occipital cortex. Another study found no difference in IMPase activity in erythrocytes of non- medicated patients compared to control group this enzyme leads to the release of free inositol therefore it is an indirect way of measuring inositol level (Shimon et al 1997).

An important intracellular enzyme in the PI path way is PKC which has been examined in many research studies in recent years. Fried man et al study showed increased platelet-PKC activity in the manic state of bipolar disorder patients. Increased serotonin-stimulated PKC activation was also found in platelets of patients in manic state, following lithium treatment these levels were returned to the same levels of control subjects thus showing that drugs which are used for treating bipolar disorder affect the PI pathway indicating that maybe the disruption of PI pathway is involved in the cause of this disorder.

Some other studies of bipolar patients have shown irregularity in the phosphoinositol/protein kinase C (PKC) signalling system. Protein Kinase C is an important intracellular enzyme in the PI signalling pathway and translocates from the cytosol to the membranes. significantly elevated levels of concentrations of 4,5-bisphosphate (PIP2) in the platelet membranes of patients in the manic phase of bipolar disorder have been observed in one study; it was also noted that the activity of platelet PKC was found to be higher in patients during a manic state of bipolar disorder (Manji & Lenox, 2000).

A summary of the results are placed in table 3 below.

Findings

Studies

Neurotransmitter studies

Serotonin

5-HIAA in BP 5HT1A receptor binding in raphe & hippocampus & amygadala of depressed patients. Serotonin uptake sites in depressed BP. Decreased levels also shown in euthymic patients.

Concentration of radioligand binding to serotonin transporter in platelets of depressed patients. Decreased 5HIAA In mania

Manji & Lenox (2000); Traskman et al (1981), swann et al (1983);Asberg et al (1984), Leake et al (1991); Maes et al (1995); Garlow et al (1999); Drevets (1999); Thakore et al. (1996)

Noradrenalin

In depressive state in mania state

Metabolite of NA (MHPG) in urinary & cerebrospinal fluid of mania compared to depression. Lower levels of NA activity indication by clonidine

Laakmann et al (1990);Manji & Lenox (2000);Goowin et al 1990, Bowden (1997);Schatzberg et al (1995);Manji et al (1997); Delgado (2000); Young et al (1994)

Dopamine

Increased/normal levels of HVA in cerebrospinal of depressed patients. Increased levels in manic state.

Gerner et al (1984);Subrahmenyam (1975); Manji et al (2000)

Signal transduction studies

G protein

High G protein levels in frontal, temporal, occipital cortex from post mortem brains. Low G protein correlated with AC. Low G protein levels with Lithium. Increased G proteins (a subunit) in lymphocytes & platelets.

Young et al (1994); Brown et al (1993); Schreiber et al (1991); Perez et al (1995); Mork et al (1992); Avissar et al (1988); Risby et al (1991); Friedman et al (1996)

cAMP

Increased levels in BP. Increased Forskolin stimulated adenylate Cyclise activity. Increased levels of cAMP dependant protein in platelets of patient

Risby et al (1993), Wright et al (1984); Wang et al (1997)

Phos

PFC levels of free inositol lower compared to control Reduced linking of inositol to PI intracellular pools in BD. Free inositol levels in frontal cortex of post mortem brains increased.

Shirmon et al. (1997); Atack et al.(1995); Banks et al (1997); Mori H et al. (1991)

10. Discussion

A major limitation of the articles is the use of cross sectional research design rather than longitudinal. Many studies adopt a cross-sectional design since (i.e. examine one state of mood) it is cheaper and easier than following participants for the whole duration of altered states. Many of the studies use smaller samples; these are insufficient basis for construction of cohesive models to integrate these findings.

What are the differences between changes directly linked to the aetiology of the disorders and changes secondary to the disorder or changes in activity consequent on the changes in mood? There is a lack of research conducted on the changes to be expected during normal mood responses. How do we define the clinical characteristics that need to be investigated biochemically do we look for correlations in the clinical disorder or within the specific states e.g. Mood agitation. The symptoms cut across different disorders it is quite difficult to establish one cause of an array of symptoms which may or may not be due to another disorder.

Biochemical assays have undergone vast improvement they are more accurate and sensitive therefore more information has been received compared to prior investigations, because of this it is hard to compare the results of earlier studies with those of recent studies. As drug treatments are constantly improving, clinical studies in understanding the functions of these treatments and influence on neurotransmitter and signalling systems will change therefore theories about the aetiology of bipolar disorder will constantly evolving.

Mood states and their characteristics cannot be quantatively defined. How can one be certain of the particular mood an individual is in? There are various levels of depression. It is important to recognize the variety of mood states because of the need to develop correct antidepressants/mood stabilizers to control these states.

There is a considerable amount of data that shows the support that shows the support of abnormalities of signalling transduction as underlying neurobiology of bipolar disorder. Specific components of the signalling pathways have been indentified on several studies providing targets for action of more efficient treatments rather than giving general treatments including antidepressants and mood stabilizing drugs.

The action of these drugs have been beneficial effects for future research; although grouping of subjects should be formed to dwell further into the bipolar subtypes and array of symptoms to find individual causes. Biochemical, pharmacological and genetic studies combined will form more concrete results, looking at one area of research is not sufficient; collaboration is the key to gaining better results.

Since all the neurotransmitter pathways are interlinked deregulation can occur on many levels and it is most unlikely that one single abnormality is the cause of this disorder. Maybe these abnormalities in the neurotransmitter circuits produce a biological vulnerability combined with any genetic defects, so when environmental factors are involved this mood disorder develops.

12. Conclusion

In answer to the initial question what are the roles of neurotransmitter and signal transduction in bipolar disorder? Most biochemical studies strongly suggest that bipolar disorder may be due to abnormalities in the neurotransmitter circuit and associated signalling transduction mechanisms. Especially function of the G protein α subunits and effectors molecule like the protein kinase C (PKC) in studies conducted in peripheral cells and post-mortem studies. Mania findings of neurotransmitter abnormality activities are less consistent. Euthymic bipolar cases show decreased serotongic activity this may be a trait for bipolar patients. Neurotransmitter studies are continually moving away from the simple diactomous model of decreased and increased levels affecting depression and mania. These relationships are, however, all contingent upon the symptoms being stable throughout the individual’s life. Until this can be verified by additional longitudinal studies any answers to the above question should be made with this in mind. The limitations highlighted along with mediating variables may weaken the relationship between neurological abnormalities and bipolar disorder. Despite the difficulties in conducting these experiments, many results have been repeatedly found in many investigations, illuminating the importance of these neurotransmitters and signal transduction mechanism abnormalities in the cause of bipolar disorder.

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