Bipolar disorder: multiple pathways to neuroprogression

People with bipolar disorder can thrive or fail to thrive. Which path they take can depend on many factors – age of onset, early trauma, severity of illness overall (number, frequency, and severity of mood episodes), inter-episodic symptoms, comorbid conditions, cognitive dysfunction, social support, diet, sleep hygiene, smoking, and even the neurotic syndrome. If one carefully examines the extant literature on the course of bipolar disorder, one will find a simple and rather uninteresting relationship: People with a greater burden of illness have a more difficult course. The more interesting question is: Beyond severity, why do some people thrive while others do not? In the past few years, a provocative hypothesis has been proposed by thoughtful researchers that people with bipolar disorder who fail to thrive experience a degeneration of their brains – with loss of dendrites, synapses, neurons, astrocytes, and glial cells over time, that is, a progression of neurotoxicity, a loss of neuroplasticity, a neuroprogression. The testable hypothesis is that neuroprogression is the cause of a worse bipolar course or at least a correlate – but what caused what? Did the neuroprogression precede the worse course or did the worse course cause the neuroprogression? One of the great dangers that researchers face is that they can fall in love with their hypotheses. If one postulates neuroprogression, then one can see it everywhere, a confirmation bias that leads to finding supportive and ignoring contradictory evidence. But like good writers, good researchers should be willing to fall out of love with their hypotheses and as William Faulkner said, ‘In writing you must kill all your darlings’. Passos and colleagues, some of whom have been great proponents of the neuroprogression hypothesis, have looked at the data on neuroprogression and have found that the evidence is quite mixed, perhaps not enough to ‘kill their darling’ but enough to call into question an overarching neuroprogression hypothesis (1). They found a large hole in the evidence for neuroprogression, that is, that most of the data are cross-sectional and not longitudinal. These data are subject to bias and if the hypothesis is to be tested, longitudinal studies of biological features of bipolar disorder are needed and are lacking. The specific bias inherent in examining cross-sectional data resides in the problem of determining causality as mentioned above – did those patients who have early or premorbid evidence of neuroprogression (cognitive dysfunction, reduced volumes in selected relevant brain areas) subsequently have a worse course of the disorder or did those who have a worse course of bipolar disorder have a greater allostatic load and systemic toxicity (2) that, in turn, caused neuroprogression? An important link to consider is allostatic load. Allostatic load represents a cumulative total body response to stress, elegantly studied and reviewed by Bruce McEwen (3, 4). It seems unnecessary and trivial to postulate that stress is bad for brain health. We all know that. In contrast, it is worthwhile to explore the details about how stress gets transduced into neurobiological changes which can lead to damage to neurons. Familiar to many readers of Acta, acute stress increases glucocorticoid levels – and acute increases may actually be neuroprotective – but sustained or repeated stress results in sustained increases of glucocorticoid levels as well as glutamate levels, resulting in neurotoxicity. Sustained stress also downregulates a wide swath of neuroprotective genes – including BDNF, VEGF – with associated decreases in neurogenesis and neuroplasticity, especially in the hippocampus as evidenced by reduced volume and function. Early trauma, in contrast to sustained stress, also dysregulates one’s response to stress so that subsequent stressors cause more distress, in part because of the ‘harmonics’ of the past echo into the present – that is, a current stimulus acts as a trigger for past traumatic stimuli and people react to the present as if it were a replay of the past – with a possible biological explanation due to faulty pattern separation and pattern completion which is dependent on neurogenesis in the hippocampus (5). Remarkably, early trauma can permanently change one’s response to stress, leading to hyperarousal and hypervigilance and sustained stress. The final aspect of allostatic load is that an imbalance of pro and anti-inflammatory cytokines occurs with profound implications for overall