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Bipolar Disorder: Drug Treatment Modalities Report


Introduction

Bipolar disorder (BD) is a mental disorder marked by a change in manic and depressive states, mixed states, and the alternation of euphoria and depression, which is also known as manic-depressive illness. Mood swings in patients with BD are more serious than those people encounter every day. In contrast to the normal change of mood, with their increases and decreases, which are inherent in any person, the symptoms of BD can lead to serious consequences (Cerimele, Chwastiak, Chan, Harrison, & Unützer, 2013). They can affect the quality of work and personal life and even cause thoughts about suicide. The alternations of mood are accompanied by significant changes in energy and behavior. The course of BD consists of the periods of the excited and passive states that are called mania and depression respectively. As for progress, the evidence shows that the disease may lead to more depressions, turn to a rapid-cycling manner, or result in functional recovery.

The symptoms of mania or manic episodes are increased energy and anxiety, euphoric mood, increased irritability, distractibility, inability to concentrate, inadequate assessment of the situation, drug abuse, especially cocaine, alcohol, and insomnia medications, and provocative, intrusive, or aggressive behaviors (Mondimore, 2014). A manic episode is diagnosed if a manic state accompanied by three or more symptoms lasts for most of the day, almost every day, and during a week or longer. The progression of the disease refers to depression or depressive episodes, during which patients tend to ponder over their behaviors and experience a sense of guilt. The key symptoms of depression include a prolonged state of sadness and anxiety, hopelessness and pessimism, the loss of interest in activities that the sick person previously enjoyed, low energy, concentration problems, difficulties in remembering or making decisions (Mondimore, 2014). Changes in appetite, chronic pain, or other persistent symptoms that are not the result of a physical illness or injury, and thoughts about death or suicide may be noted. A depressive episode is diagnosed if five or more symptoms frequently appear for two or more weeks on an everyday basis.

The recent epidemiological studies revealed the greatest prevalence of BD in the age group from 18 to 24 years, and without sex differences (Rowland & Marwaha, 2018). The appearance of the given disease at a later age, as a rule, is a consequence of traumatic brain injury, a stroke, et cetera. Rowland and Marwaha (2018) also mention that the lifetime prevalence of the bipolar disorder is 2.4 percent, while it may vary in various countries, depending on age, ethnicity, and other factors. The higher socioeconomic status and creativity are associated with lower risks of developing the disease.

Theory

Neurons have special ways to communicate with each other, the so-called projections of axons and dendrites. The gap between them composes the synaptic cleft, where the interaction of neurons occurs. Neurotransmitters are synthesized in the cells and delivered to the end of the axon – to the presynaptic membrane (Harrison, Geddes, & Tunbridge, 2018). Under the impact of electrical impulses, they enter the synaptic cleft and activate the receptors of the next neuron. This explains the core of neurotransmitters and receptors theories that will be used to understand the biological nature of BD in an in-depth manner. The pivotal biological cause of BD is the chemical imbalance expressed in a disruption in the production and synthesis of dopamine and serotonin neurotransmitters. At the chemical level, the disparity of neurotransmitters in the brain, namely, a reduced level of serotonin and noradrenaline and an increased rate of dopamine should be noted.

Dopamine, a neurotransmitter responsible for mood, shows an increased transmission at the time of the manic phase. It can be assumed that a rise in the level of dopamine causes a reduction in the secondary homeostatic regulation of the main systems and receptors, which, in turn, promotes an increase in the quantity of G-protein coupled receptors (Ashok et al., 2017). Furthermore, a decrease in dopamine transmission for the period of depression occurs. The depression period ends with the rise of homeostatic regulation, and the cycle is then repeated. It was found that two more types of neurotransmitters can cause severe changes in mood, such as gamma‐aminobutyric acid (GABA) and glutamate. In people with bipolar disorder, GABA is found in higher concentrations, and the disease leads to a decrease in GABA-beta receptors (Brady et al., 2013). The levels of glutamate significantly increase in the left dorsolateral prefrontal cortex during the manic phase of bipolar disorder and normalize after the end of the phase.

Dopamine receptor stimulants, also known as agonists, duplicate the effects of natural dopamine. They bind to the D2 and D3 receptors in the nigrostriatal dopaminergic pathway, which extends from the substantia nigra to the basal ganglia and the striatum (Ashok et al., 2017). A new generation of drugs that stimulate D1 receptors is under development. Dopamine receptor agonists are expected to counteract apathy and blunting cognitive abilities, while antagonists should be reduced in the course of the treatment.

Norepinephrine is a neurotransmitter that acts as an energy promoter, which is also used while making quick decisions. It is activated under stress and in extreme situations, causing a surge of energy, reducing the feeling of fear yet increasing the level of aggression (Harrison et al., 2018). The SLC6A2 gene encodes a norepinephrine transporter protein by providing norepinephrine’s reuptake in the presynaptic membrane. The latter determines how long norepinephrine will act in the human body after he or she successfully handled a dangerous situation. When the neuron is functioning normally, it releases norepinephrine into the synaptic cleft, the space between two neurons. Noradrenaline binds to the α1–, α2– and β1– receptors on the postsynaptic membrane – the neuron membrane on the other side of the synapse (Harrison et al., 2018). This binding is transmitted to the cell, which activates certain genes that regulate the activity of proteins, which, in turn, determine all the activity of a neuron. Alpha-2 agonists of Norepinephrine cause the sedating impact, and its antagonists are used as tricyclic antidepressants, antipsychotics, and beta-blockers.

Serotonin is a neurotransmitter that not only brings positive emotions but also reduces susceptibility to negative ones. It provides support to related neurotransmitters, including norepinephrine and dopamine. Serotonin is released into the synaptic cleft in the same way as norepinephrine. For serotonin, there are 17 different types of receptors, which emphasize its importance as a neurotransmitter. Also, it improves the accuracy of the transmission of active signals in the brain and assists in concentrating. The monoamine oxidase A enzyme (MAOA) is responsible for the deactivation of monoamines, neurotransmitters with one amino group, which includes adrenaline, norepinephrine, serotonin, histamine, and dopamine. The better the MAOA gene works, the faster the stressful situation is neutralized, and the faster a person becomes able to make informed decisions. Some agonists of serotonin provide an antidepressant-like effect (5-HT 2B) likewise such antagonists as 5-HT2C and 5-HT3A.

The evidence shows that the brain of patients with bipolar disorder is different from that of a healthy person. The severity of these changes is still unknown, but they can shed light on the causes of this disease. For example, neurotransmitters that control mood can play an important role in the development of the bipolar disorder. The increase in the level of GABA seems to be caused by a disorder at the early stages, as well as a violation of cell migration, the formation of normal detachment, and stratification of brain structures, usually belonging to the cerebral cortex (Kim, Santos, Gage, & Marchetto, 2017). The thinning of the cortex was revealed in patients compared with the control group, with the greatest deficiency observed in the areas responsible for inhibition and motivation, namely, the frontal and temporal areas.

Treatment

According to research results, patients with bipolar disorder undergoing treatment are at risk of developing mania, hypomania, or a rapidly circulating form of the disease (Mondimore, 2014). To protect patients with BD from such consequences, it is necessary to use mood-stabilizing drugs, either in combination with antidepressants or separately. Currently, lithium and valproate are considered the most common mood-stabilizing drugs. Nevertheless, experiments are continuing to assess the effectiveness of the use of new drugs compared to the existing ones (Geddes & Miklowitz, 2013). The treatment options are mood stabilizers that help in eliminating rapid emotional changes, antidepressants, and antipsychotic drugs that are prescribed together with mood stabilizers with vivid symptoms during the manic phase if a patient has a loss of contact with reality.

Risperidone (Risperdal) is an antipsychotic medication that selectively blocks 5-HT2-serotonergic, D2-dopaminergic, and alpha1-adrenergic receptors. It also interacts to a lesser extent with alpha2-adrenergic and histamine H1-receptors in the central nervous system. Risperidone has poorly expressed an affinity for 5-HT1A-, 5-HT1C-, 5-HT1D-serotonergic, and D1-dopaminergic receptors as well as haloperidol sensitive sites of sigma binding (Geddes & Miklowitz, 2013). The given medication cannot interact with m-cholinergic and beta2-adrenergic receptors. It has antipsychotic, sedative, antiemetic, and hypothermic effects that occur due to the blockade of the D2-dopaminergic receptors of the mesolimbic and mesocortical systems. The sedative action is a consequence of blockade of adrenoreceptors of the reticular formation of the brain stem, and hypothermic impact is caused by the blockade of the dopamine receptors of the hypothalamus. Risperidone is known to suppress delirium and hallucinations as well as reduce the feeling of fear and aggressiveness.

The absorption of Risperidone is quick and complete, while food does not affect the fullness and speed of absorption. Risperidone Tmax is one hour 1 h, 9-hydroxyrisperidone – three hours with high activity of CYP2D6 isoenzyme and 17 hours with low activity (Geddes & Miklowitz, 2013). Risperidone plasma concentration is proportional to the dose of the drug; the equilibrium concentration of the medication in most patients is achieved within one day. Risperidone is rapidly distributed in the body, penetrating the central nervous system and breast milk – the volume of distribution 1-2 liters/kg. The half-life of risperidone is three hours, and it is excreted by the kidneys in the form of the pharmacologically active fraction and the intestine. The complete elimination may be prolonged up to 20 hours, depending on a patient’s health condition.

Contraindications include hypersensitivity, lactation period, and children’s age up to 15 years since efficiency and safety have not been established to this category of patients. The side effects may be determined by a patient’s overall conditions, sensitivity to the drug, and other factors. The central nervous system presents the most of the side effects: insomnia, anxiety, headache, drowsiness, fatigue, dizziness, blurred vision, extrapyramidal symptoms, mania or hypomania, stroke, and neuroleptic malignant syndrome (Geddes & Miklowitz, 2013). At the same time, constipation, dyspepsia, vomiting, abdominal pain, hypo-salivation or hypersalivation, orthostatic hypotension, reflex tachycardia, priapism, erectile dysfunction, and urinary incontinence may be enumerated among the most common issues. As for the interactions, the given medication reduces the effect of levodopa and other dopamine agonists. Phenothiazines, tricyclic antidepressants, fluoxetine, and beta-blockers may increase plasma risperidone concentrations. Nonadherence to Risperidone creates additional risks, which should be clarified to patients immediately to make them aware of their condition and receive informed consent to continue the treatment.

A new antipsychotic medication, Cariprazine is currently undergoing clinical trials for indications for the treatment of the bipolar disorder. The drug provided by Gedeon Richter and jointly developed with Forest Laboratories and Mitsubishi Tanabe Pharma refers to piperazine/piperidine derivatives (Citrome, 2013). Cariprazine has partial D2 and D3 receptor agonist, which explains its positive impact on patients with BD. The molecules of the medication act, on the one hand, as a partial agonist of the dopamine receptors D3, D2L, and D2S, as well as the serotonin receptor 5-HT1A, on the other hand, as an antagonist of the serotonin receptors 5-HT2B and 5-HT2A. The D2 and D3 receptors are important targets since their excessive stimulation is implicated (Citrome, 2013). The increased selectivity of Cariprazine to D3 receptor reduces side effects, especially extrapyramidal symptoms that are frequent with the administration of other neuroleptics, and is also reflected in the form of positive pro-cognitive manifestations.

Although it is emphasized that second-generation antipsychotics have advantages compared to traditional drugs for the relief of negative symptoms, this difference was largely due to the dynamics of secondary negative symptoms (Severus et al., 2014). Cariprazine, which has a high affinity for D3 receptors, was designed to create a new antipsychotic drug that has therapeutic activity against negative symptoms and cognitive impairment in patients with BD. The results of preclinical studies show that the drug has a certain pro-cognitive and anti-anhedonic efficacy (Citrome, 2013). Thus, Cariprazine contributes to mitigating impaired working memory, attention, and recognition ability.

The given medication is captivated from the gastrointestinal tract, achieving a peak concentration within 3-4 hours after ingestion. With prolonged use, it accumulates in the plasma, but in the dose range of 1-18 mg, its concentration in the blood increases in proportion to the dose taken (Citrome, 2013). The half-life of Cariprazine is approximately six days, and the route of elimination is urine. After Cariprazine absorption behaves as a lipophilic antipsychotic, it is widely distributed in the tissues. In rat studies, its brain concentration was eight times higher than the plasma concentration. Metabolism of the drug occurs in the liver with the participation of cytochrome P450 CYP3A4 and, to a lesser extent, 2D6. Since the drug was not fully tested, it is ethical to avoid its prescription to children and adolescents whose central nervous system is especially vulnerable to negative impacts.

The side effects of Cariprazine include extrapyramidal symptoms, headache, dizziness, constipation, nausea, vomiting, diarrhea, blurred vision, hyperthermia, drowsiness, and insomnia. An increase in the level of prolactin and prolongation of the QT interval in the trials did not reach clinical significance. A noticeable increase in weight was observed in a significantly smaller number of patients than when receiving risperidone, although this figure was higher than when taking a placebo (Citrome, 2013). With the prolonged use, a potentially clinically significant weight gain was detected in a third of patients during the studies. However, there is no sufficient experience of its use for the treatment of cognitive disorders in a long-term period.

Lithium (Eskalith, Lithobid) is a mood-stabilizing drug that is often used to stabilize a patient’s mood. Severus et al. (2014) state that it helps to control the symptoms of acute mania and effectively prevents the recurrence of periods of mania and depression. The pharmacological action contains antipsychotic, normothermic, and sedative effects. Lithium blocks sodium channels in neurons and muscle cells and causes a shift of intraneuronal catecholamine metabolism. It is fully absorbed in the gastrointestinal tract, and the T max is 6–12 hours (Severus et al., 2014). The half-life period increases from 1-3 days after the first dose to 2-4 days after one year of regular intake. Lithium penetrates through the placental barrier and into breast milk, and its elimination occurs through urine. In terms of the exceptional treatment conditions and the ethical implications for high-risks, care providers should especially alert due to the toxicity of Lithium.

The common side effects include weight gain and digestive problems. The drug can also affect one’s thyroid and kidneys – periodic blood tests are needed to monitor the condition of the mentioned organs. Lithium is a category D drug, which indicates that it should be avoided during pregnancy, if possible. However, in some cases, the benefits may outweigh the potential risks. Contraindications also involve hypersensitivity, severe surgery, cardiovascular diseases, epilepsy, and Parkinsonism due to the neurotoxic effect of lithium (Severus et al., 2014). Leukemia in history and dehydration increases the risk of lithium toxicity. As for interaction, when carbamazepine is combined with Lithium, the risk of neurotoxic effects increases. Metronidazole, fluoxetine, diuretics, NSAIDs, and ACE inhibitors slow down kidney removal of Li + and increase its toxic effects. Lithium tends to reduce the pressure of norepinephrine and increase or prolong the blockade of neuromuscular transmission when combined with besylate atracurium or pancuronium bromide.

Conclusion

To conclude, the main theory associated with the BD is the imbalance of neurotransmitters and receptors, which is understood as a low level of serotonin and noradrenalin and a high rate of dopamine. Such an imbalance leads to the fact that the improper interaction of neurons in the human body impacts a patient’s behaviors and overall well-being. The key advantage of the discussed theory is its precise attention to biological issues that accompany the disease, while its disadvantage lies in the failure to clarify gaps existing in the literature. There are a lot of side effects and contraindications that set the direction for future research in the field of neurotransmitters theory – the search for the most relevant treatment option with a minimum of side effects. Thus, the risk-benefits perspectives should be assigned a top priority both for drug prescription and research studies.

References

Ashok, A. H., Marques, T. R., Jauhar, S., Nour, M. M., Goodwin, G. M., Young, A. H., & Howes, O. D. (2017). The dopamine hypothesis of bipolar affective disorder: The state of the art and implications for treatment. Molecular Psychiatry, 22(5), 666-679.

Brady Jr, R. O., McCarthy, J. M., Prescot, A. P., Jensen, J. E., Cooper, A. J., Cohen, B. M.,… Öngür, D. (2013). Brain gamma‐aminobutyric acid (GABA) abnormalities in bipolar disorder. Bipolar Disorders, 15(4), 434-439.

Cerimele, J. M., Chwastiak, L. A., Chan, Y. F., Harrison, D. A., & Unützer, J. (2013). The presentation, recognition and management of bipolar depression in primary care. Journal of General Internal Medicine, 28(12), 1648-1656.

Citrome, L. (2013). Cariprazine in bipolar disorder: Clinical efficacy, tolerability, and place in therapy. Advances in Therapy, 30(2), 102-113.

Geddes, J. R., & Miklowitz, D. J. (2013). Treatment of bipolar disorder. The Lancet, 381(9878), 1672-1682.

Harrison, P. J., Geddes, J. R., & Tunbridge, E. M. (2018). The emerging neurobiology of bipolar disorder. Trends in Neurosciences, 41(1), 18-30.

Kim, Y., Santos, R., Gage, F. H., & Marchetto, M. C. (2017). Molecular mechanisms of bipolar disorder: Progress made and future challenges. Frontiers in Cellular Neuroscience, 11(30), 1-15.

Mondimore, F. M. (2014). Bipolar disorder: A guide for patients and families (3rd ed.). Baltimore, MD: Johns Hopkins University Press.

Rowland, T. A., & Marwaha, S. (2018). Epidemiology and risk factors for bipolar disorder. Therapeutic Advances in Psychopharmacology, 8(9), 251-269.

Severus, E., Taylor, M. J., Sauer, C., Pfennig, A., Ritter, P., Bauer, M., & Geddes, J. R. (2014). Lithium for prevention of mood episodes in bipolar disorders: Systematic review and meta-analysis. International Journal of Bipolar Disorders, 2(1), 15-32.

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