The Lithium Membrain by Anne Naylor. Lithium coursing through veins in the brain (blue) provides mood stability by acting as a membrane that prevents the effects of the various faces of the illness (circles) on the brain (neural networks).
(Copied with permission from: Anne Naylor and Malhi, G. S. “Lithium therapy in bipolar disorder: a balancing act?” The Lancet 2015 386(9992): 415-416.)
Metaphors are helpful short-hands that enable us to visualize complicated relationships in simple, schematic ways. The monoamine theory of depression suggested a basic deficit model of catecholamine neurotransmitter dysfunction in depression: simply too little norepinephrine and /or dopamine . Antidepressants worked by increasing the levels of these communication molecules. Using this theory, you can almost see the low markings on the oil dipstick or the gas tank gauge and know that a fill-up will solve the problem. This visual depiction of depression has had a long, useful run and has helped many patients envision their illness and supported their willingness to use medications to fight these chemical shortfalls.
But what of lithium and its role in manic depressive illness? What’s a simple picture of bipolar pathophysiology and the beneficial effects of lithium? What do we tell our patients when they ask: how does lithium work?
In confronting this question, it is immediately apparent that the situation is more complicated with bipolar disorder than with depression. First, bipolar disorder is simply more pleomorphic than unipolar depression. It includes a range of pathology from manic to depressive and mixed states, the increased propensity for relapse, the intrinsic switch process between states, the higher levels of persistent subsyndromal symptoms, and the increasingly recognized cognitive impairment and neurodegenerative changes associated with disease progression.
In keeping with this more complicated picture, lithium has multiple effects on manic depression including acute anti-manic properties, slower antidepressant activity, prevention of both manic and depressive relapse, anti-suicidal effects, and neurotrophic and neuroprotective impact. Each of these actions proceeds with a distinct time course. This multiplicity of effects tells us that any simple, up-down or deficit-correction model of lithium’s mechanism of action in this disease is bound to be grossly misleading.
This report draws on three recent articles that review the pathophysiology of bipolar disorder and related data about how lithium works its magic [2-4]. While approaching this topic from slightly different angles, the shared themes and overlap of these works far outweighs their differences. In addition to these three review articles, I’ll also reference an utterly fascinating new experimental study from Nature that highlights lithium’s novel neuromodulatory role . The overall objective here is to achieve a simple, coherent narrative that explains this unique ion’s mechanism of action.
Given that lithium acts at multiple different levels throughout the nervous system, we’ll start at the cell membrane, the basic border which supports the overall structural and functional integrity of the cell. From there, we’ll move to cellular communication, starting with intercellular, neurotransmitter-based signaling. We will then proceed to the intracellular translation or transduction of those signals via internal, second messenger systems; this will lead us to the ultimate target of cell signaling which is the alteration of the cell’s genetic instructions, it’s DNA, through the action of transcription factors. Finally, we’ll move from the individual cell to take a look at larger, more macroscopic aspects of brain structure in bipolar disorder. Each step of the way, we’ll examine the role of lithium in addressing these different levels of dysfunction. To help us understand these complex processes, we will refer to the metaphor of the brain as a complex estate, requiring the work of many to maintain its upkeep.
- Intracellular electrolyte balance. This involves maintaining the right gradient of ions –sodium, potassium, calcium and others – between the intra- and extracellular spaces; the inside and outside of the cell. Proper gradients are necessary for optimal functioning of the cell. Imagine this like the walls of a house and the maintenance of air flow. The ideal structure will contain the optimal number and size of windows and doors to allow ventilation that is not too easy but not too difficult. Too many openings and the house won’t provide adequate containment; too few, it will become a hermetic cave. Some of the earliest and most replicated findings on pathophysiology in bipolar disorder describe disturbed ion gradients – specifically, increased intracellular sodium and calcium – in the neurons of bipolar patients resulting in impaired activity. These ion gradations are maintained through the action of special chemical pumps located in the cell membrane which act to shift ions into or out of the cell. Now it gets complicated: the operation of that cell membrane pump requires energy. Energy to power those pumps comes from an intracellular organelle called a mitochondrion, which is a small energy factory located in all cells. When the mitochondria function normally, the cell has the energy to shift these ions at the appropriate rates to achieve and maintain optimal ion gradients. When mitochondrial energy sources are impaired, the pump falters, the gradients bleed, and cellular functioning becomes disturbed. There is extensive recent data of reduced mitochondrial energy generation in bipolar disorder [6, 7]. Whether acting at the level of the membrane or the actual energy supply, lithium has been found to lower intracellular concentrations of sodium and calcium in overactive neurons.
- Neurotransmitter systems. Here we return to the catecholamine and other chemical messenger molecules that enable communication between nerve cells. Lithium acutely increases serotonergic transmission which may mediate its antidepressant effect. It has an interesting, slower and dual effect, opposing excess excitatory glutamatergic signaling and stimulating inhibitory GABA-ergic activity. As such, it tends to modulate extremes bringing the overall level of central nervous system buzz towards a balanced middle.
- Second messenger systems. Time to extend our metaphor. Think of the monoamines as letters that are sent between different households. Think of a large estate, a mansion, with staff of many kinds – landscaping, housekeeping, security – each with their own policies and procedures. The letters carry instructions on how the estate should modify its existing routines: Mow the grass less often, use a different cleaner for the bathrooms, add alarms on all the windows, etc…. These internal household procedures are equivalent to a cell’s second messenger systems: a vast set of inner regulatory pathways that govern what and how a cell carries out its mission. For example, one pathway might be analogous to the budgeting practices which determines how much money is spent, levels of discretionary income, and rules for saving. Other pathways might reflect housekeeping, repair and caretaking routines. Each has significant effects on how the entity functions. In cellular terms, these inner workings involve the operation of dozens of complicated, intersecting enzymes and protein synthesis sequences. In this metaphor, the letter carries the information or the signal to the mansion; this is cell signaling. The execution of the letter’s instructions, which involves change in the facility procedures, is referred to as signal transduction. The image below conveys the dizzying complexity of this second messenger system trafficking. Hold on to a chair as you look at this.
The major intracellular pathways that are modified by lithium involve protein kinase A, adenylate cyclase (AC), glycogen synthase kinase 3 beta (GSK-3B), protein kinase C, and the phosphoinositide (PI) cycle. Each have a cascade of downstream effects on cellular functioning, ranging from modulating neuronal excitability, regulating neurotransmission, and increasing mitochondrial energy generation, to more structural effects on brain growth which I’ll get to shortly. Of these identified pathways, over-activity of GSK-3B and the PI cycle are most strongly linked to the pathophysiology of manic depression. Lithium has been found to inhibit the activity of the former and dampen the PI cycle resulting in reduced myoinositol production. These second messenger system dysfunctions and their correction by lithium are two of the most empirically supported mechanisms of action of this drug.
- Transcription factors. Let’s return to the mansion metaphor. Each estate has its own charter that determines what it is and what it does. One might be a primary dwelling for a family, another might focus on raising horses, and a third might function as a museum. For a cell, this basic charter resides in, and is determined by, its DNA. Transcription factors are intracellular molecules that determine how these genetic policies will be carried out. When neurotransmitter signaling results in a change in a cell’s basic genetic programming – move the family out and start renting the place, change the landscaping and let the grounds grow wild, close the museum wing – this is the ultimate level of impact. The major transcription factor implicated in bipolar disorder is CREB: cyclic AMP response element-binding protein. Activation of CREB results in increases in neurotrophic factors which support brain growth and reductions in apoptotic molecules which cause cell death. Here too, lithium has been shown to modify CREB transcription activity.
- Mitochondrial energy production. This point deserves more emphasis. As mentioned, the mitochondria are intracellular structures that function as energy powerhouses. They do this through a complicated chemical process called cellular respiration that ultimately produces the compound that fuels most cellular functions, ATP. This energy pathway also clears the cell of harmful molecules, free radicals, that cause damage and death to neurons. In estate terms, the mitochondria are the generators that power the operation. When they falter, the electricity shorts out, the lights flicker, and the heat dwindles. If persistent and severe, the entire estate can become rundown and decrepit. Numerous and increasing studies, using a variety of methodologies, are documenting mitochondrial dysfunction in manic depression [6,7]. Related evidence indicates that lithium, acting through several pathways, corrects this impairment, thereby restoring energy production and all it powers – neurotransmission, maintenance of ion gradients, and regulation of cell excitability – along with reducing free radicals which results in enhanced cell survival.
- So far, this review has emphasized cellular functioning and its residential analogue, estate operations: what is done, how, regulatory actions, and procedural routines. The other major dimension of the central nervous system is the structure itself: the number and size of neurons, the number and size of glia (a type of matrix support cell in the brain), their respective growth, retraction and resilience to withstand injury; and how the growth of these individual cellular units affects the structure and functioning of larger brain areas and brain circuits. This corresponds to the size and health of our home compound, it’s grounds, and interactions with other estates. What’s this got to do with bipolar disorder? Answer: brain structure is diminished in this disease. Specifically, the size of the brain areas that mediate emotional experience and emotional regulation have been found to be smaller in those patients with this illness. This includes the prefrontal cortex, the amygdala, the hippocampus, the striatum, and the anterior cingulate. There’s a silver lining though: lithium reverses this shrinkage; it grows brain tissue. Neuroimaging and post-mortem studies document this remarkable fact. Through a combination of growth promotion (neuroproliferation) and neuroprotective actions, lithium counteracts the neurodegenerative changes associated with this disease. In their 2009 paper, Machavado-Viera and colleagues from the NIMH assert that this is the final, convergent pathway for lithium’s therapeutic action. All operations ultimately support the structural integrity of the estate. If the estate functions well, it grows, develops, spreads and establishes more connections with other homes. If various communication and procedural pathways are compromised, the residence withers and may shut down altogether. How does lithium accomplish this astonishing feat?
Several of the second messenger systems described earlier generate molecules that have either neurotrophic or neurodegenerative effects. The primary neurotrophic molecules are brain derived neurotrophic factor (BDNF) and the anti-apoptotic protein, B-cell lymphoma 2 (Bcl-2). The structural bad guys are GSK-3B, the free-radicals mentioned earlier, intracellular calcium, and a host of other culprits.
- “Excitable Boy, they all said, Excitable Boy” (Zevon, W; 1978). Using an entirely new experimental procedure, Mertens and colleagues published a report in Nature in 2015 that attempted to clarify the mechanism of action of lithium. They removed easily-obtainable connective tissue fibroblast cells from 6 patients with bipolar disorder and 4 unaffected individuals. They then de-differentiated these cells, wiping their genetic operating systems clean, and bringing them back to their original, pluripotent state; the state which all cells are in before they got slotted and programmed into their various specialist roles. From there the cells were then induced or reprogrammed to become hippocampal neurons, one of the cell types that has regularly shown dysfunction in bipolar disorder. This induced pluripotent stem cell technology enabled them to compare the hippocampal neurons derived from bipolar patients to those from a non-ill comparison group. Here’s what they found. First, the bipolar hippocampal neurons showed abnormalities in the expression of a number of genes, but especially the genes regulating mitochondrial size and function. Second, the bipolar hippocampal neurons were hyperexcitable; they responded to signals at lower thresholds and with greater chemo-electric responses than control neurons. Last, and most mind-blowing, this hyperexcitability was controlled by lithium, but only among the hippocampal neurons derived from the bipolar patients who were clinical responders to lithium. Is hippocampal neuron excitability an endophenotype – the molecular expression – of bipolar disorder?
Where does this review leave us? We have described a multifaceted picture of bipolar pathophysiology, circa 2016, that includes cell membrane abnormalities, disturbed ion gradients, impaired neurotransmission, aberrant second messenger system signal transduction pathways, transcription factor changes, corrupted mitochondrial function and energy dynamics, neuronal loss and shrinkage in emotion-mediating pathways, and hippocampal neuronal excitability. (One area which we did not cover was inflammatory changes that are also receiving great attention in our field). In this review, we’ve tried to use the metaphor of a residential estate
- a vast country home with numerous departments involving housekeeping, landscaping, repair, energy generation, and communications
- to enable imagination of this complex cellular entity. No easy task. If we stick with this metaphor, what does it suggest for our initial question about what we tell our patients when they ask how lithium works?
Help wanted: Seeking a handy, versatile molecule that can help with all aspects of the management of our large, complex residential estate. These responsibilities will include border patrol, gatekeeping, oversight of all household departments and procedures, communication systems, landscaping, facilities management, power generation, security and protective services, and the repair and expansion of the grounds. This is an enormous, multifaceted job but one which is eminently manageable by the right party. In short, we’re looking for that special, unique molecule with whom we’ll have a perfect chemistry.
John Gottlieb, M.D.