In this discussion, we will discuss the pathophysiology of bipolar disorders and the mechanisms of action of mood stabilizers.
Bipolar Disorder Etiology
Bipolar disorder is considered the most heritable psychiatric disorder from studies of identical twins, where up to 40-70% of identical twins both have bipolar disorders. There seems to be a pronounced genetic overlap, primarily between schizophrenia, bipolar disorder, and major depressive disorder.
While, as discussed in CNS 19, gender representation is equal, there are some differences between males and females.
Female:
- More depressive in nature than males.
- More co-morbid with anxiety and eating disorders
- More thyroid problems and augmenting thyroid treatment with bipolar treatment can help
Male:
- More attempted suicide
- More mania episodes
- More rapid cycling of episodes
One Caveat about Bipolar Studies
Most of the bipolar imaging has been conducted in patients in euthymic or depressive states because it is difficult to manage manic patients and maintain minimal head motion.
The imaging that has been obtained suggests that bipolar disorder is a progressive illness. This is consistent with the MRI study where bipolar patients were observed to have larger lateral ventricles.
Proposed Brain Alteration in Bipolar Patients
- An aberrant ventral prefrontal activity in bipolar patients. This can compromise the ability to adapt to changes and social circumstances.
- A decreased activity in the dorsolateral prefrontal cortex. This can compromise working memory and impaired ability to sustain attention and compromise executive function.
- The prefrontal cortex works together with the dorsal ACC and parietal cortex to regulate the limbic structure, which is the control center of emotion and behaviors. This complex is considered the executive cognitive complex.
- Decreased glial cells (astrocytes and oligodendrocytes) in the prefrontal cortex
- There are neuronal changes that lead to cell deaths and apoptosis and thinning of the neuropil
- 22% of patients have decreased neuronal density in the dorsolateral prefrontal cortex
- Bipolar patients have a higher number of norepinephrine neurons and a deficit of serotonergic neurons.
MRI studies were done to look at the cortical thickness of healthy individuals, bipolar individuals, and MDD individuals. In comparing the healthy scan to the bipolar scan, there is a decrease in cortical thickness in six regions (mostly in the frontal, parietal, and posterior cingulate cortex.) When comparing bipolar scans with MDD scans, the same differences were even more pronounced.
The PET imaging study looked at glucose uptake during the manic and depressive phases. There was a marked increase in glucose uptake during the manic state and less uptake during the depressive state.
Physiology of Bipolar Disorder
The bipolar symptoms manifested in emotion, behavior, autonomic, endocrine, and cognitive functions. It is a complex network.
The prefrontal-limbic network, consisting of the hippocampus, amygdala, and thalamus, seems to be vital because it regulates the autonomic/internal emotional regulatory network and the volitional/external regulatory network.
One of the potential biomechanism of bipolar was derived from the mechanism of lithium, the phospho-inositide pathway.
In this pathway, Gq protein is activated, leading to the activation of secondary messengers, IP3 and DAG. IP3 causes an increase in intracellular calcium. This pathway is hyperactive in bipolar disorder, as seen in the high level of IP3 and elevated intracellular calcium.
Lithium inhibits the recycling of IP3 back to the PIP, the protein precursor.
There is a thought that if we can control the intracellular calcium level, we can treat bipolar disorder. The proposed mechanism is through the L-type calcium channel antagonism, but the evidence hasn’t been overwhelmingly positive.
Another approach to bipolar disorder treatment has been to look at the cytokines, glial markers, and genes. There are some genes that are critical in synapses, bio-transport, recycling, and stabilization of nodes of Ranviers that seem to be potential therapeutic targets.
Metabolic diseases, such as obesity, diabetes, and cardiovascular diseases, can also play a role in impacting the pathophysiology of bipolar disorder.
Treatment of Bipolar Disorder
The medications used in bipolar disorder is referred to as mood stabilizer. Originally, this was referred to medications that treat mania and prevent recurrent mania. More recently, this term has been used for a wide range of medications that act like lithium to anticonvulsants.
Some agents are considered to be mania-minded and stabilize the mood from above to prevent symptoms of mania. Others are considered to be depression-minded and stabilize the mood from below and prevent bipolar depression as well as prevent the relapse of depression.
Lithium
Bipolar disorder has been treated with lithium classically. Lithium is an ion whose mechanism of action is not well-defined. Some of the mechanisms are believed to affect signal transduction of the PI pathway, as mentioned above. Other pathways include the neuro-tropic factor, which promotes neuro-protection and plasticity, and the GSK-3b protein.
The GSK-3b is a glycogen synthase kinase that may be a putative therapeutic target for bipolar disorder. It is involved in a lot of intra-cellular pathways, such as insulin signaling, neurotropic signaling, and Wnt glycoprotein signaling.
GSK-3b is important. It has been shown that an increase in this protein leads to neuronal degeneration, cell death, apoptosis, weakening plasticity, and a reduction in cellular resilience. The mechanism behind this is currently unknown.
Because lithium inhibits this protein, it is one of the reasons that lead to an improvement in bipolar disorder symptoms.
Interestingly the use of antidepressants can cause deficiencies in signals that maintain the inhibition of GSK3, leading to an up-regulation of GSK3. This promotes the patient’s susceptibility to depression and mania.
Lastly, lithium has been shown to alter gene expressions, such as myelination genes, clock genes, and synaptic vesicle genes. Not much is known currently on this.
Lithium can have significant side effects.
Some acute effects include:
- Nausea and diarrhea
- Lethargy
- Impaired cognitive
- Hand tremor
Some long-term side effects include:
- Hypothyroidism
- Lithium accumulates in the thyroid tissues and reduces iodine uptake by the thyroid, and interferes with thyroxine synthesis. This leads to an inhibition of thyroid hormone secretion and hypothyroidism.
- Weight gain
- leukocytosis
- Dermatological effects
Other Treatment Options
Valproic acid is an anticonvulsant that interferes with voltage-sensitive sodium channels. The inhibition leads to an increase in GABA activity, which reduces the downstream signal transduction cascade. It may also interact with the calcium channel and blocks the glutamate channel. Valproic acid is teratogenic.
Carbamazepine and lamotrigine have also been used. These medication work by binding to the alpha subunit of voltage-sensitive sodium, calcium, and potassium channels. Lamotrigine reduces the release of glutamate through the blockage of sodium channels.
Atypical antipsychotics can be effective in treating mania and maintenance treatment. These medications include aripiprazole, olanzapine, risperidone, ziprasidone, and lurasidone. These medications work through dopamine-2 receptor antagonism, 5-HT2 antagonism, and 5-HT1A agonism.
The best evidence-based combination is lithium or valproic combined with an atypical antipsychotic. Never combine lamotrigine with valproic acid due to the SJS risk.
Other less common medications for bipolar disorders include:
- Topiramate (anticonvulsant)
- Gabapentin and pregabalin – help with pain and insomnia but have little to no action as mood stabilizers.
- Riluzole – prevents glutamate release. It has been linked with frequent liver function abnormalities.
- Benzodiazepines
- Modafinil
Mood Stabilizers Under Development
Tamoxifen is a protein kinase C inhibitor currently being used in the treatment of breast cancer.
Endoxifen is an active metabolite of tamoxifen with four times greater PKC inhibition.
Repetitive transcranial magnetic stimulation is being investigated as well, particularly in those with rapid cycling bipolar disorder.