Biologic – Mental Health Matters

An Overview of the Biology of Depression

Published on 03/24/2022 by Andrew MarshallLeave a comment

Introduction

Scientific studies have found that different brain areas show altered activity in people with major depressive disorder (MDD), and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes.

Factors spanning these causative groups include nutritional deficiencies in magnesium, vitamin D, and tryptophan with situational origin but biological impact. Several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around monoamine neurotransmitters, neuroplasticity, neurogenesis, inflammation and the circadian rhythm. Physical illnesses, including hypothyroidism and mitochondrial disease, can also trigger depressive symptoms.

Neural circuits implicated in depression include those involved in the generation and regulation of emotion, as well as in reward. Abnormalities are commonly found in the lateral prefrontal cortex whose putative function is generally considered to involve regulation of emotion. Regions involved in the generation of emotion and reward such as the amygdala, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and striatum are frequently implicated as well. These regions are innervated by a monoaminergic nuclei, and tentative evidence suggests a potential role for abnormal monoaminergic activity.

Genetic Factors

Difficulty of Gene Studies

Historically, candidate gene studies have been a major focus of study. However, as the number of genes reduces the likelihood of choosing a correct candidate gene, Type I errors (false positives) are highly likely. Candidate genes studies frequently possess a number of flaws, including frequent genotyping errors and being statistically underpowered. These effects are compounded by the usual assessment of genes without regard for gene-gene interactions. These limitations are reflected in the fact that no candidate gene has reached genome-wide significance.

Gene Candidates

5-HTTLPR

The 5-HTTLPR, or serotonin transporter promoter gene’s short allele, has been associated with increased risk of depression; since the 1990s, however, results have been inconsistent. Other genes that have been linked to a gene-environment interaction include CRHR1, FKBP5 and BDNF, the first two of which are related to the stress reaction of the HPA axis, and the latter of which is involved in neurogenesis. Candidate gene analysis of 5-HTTLPR on depression was inconclusive on its effect, either alone or in combination with life stress.

A 2003 study proposed that a gene-environment interaction (GxE) may explain why life stress is a predictor for depressive episodes in some individuals, but not in others, depending on an allelic variation of the serotonin-transporter-linked promoter region (5-HTTLPR). This hypothesis was widely-discussed in both the scientific literature and popular media, where it was dubbed the “Orchid gene”, but has conclusively failed to replicate in much larger samples, and the observed effect sizes in earlier work are not consistent with the observed polygenicity of depression.

BDNF

BDNF polymorphisms have also been hypothesized to have a genetic influence, but early findings and research failed to replicate in larger samples, and the effect sizes found by earlier estimates are inconsistent with the observed polygenicity of depression.

SIRT1 and LHPP

A 2015 GWAS study in Han Chinese women positively identified two variants in intronic regions near SIRT1 and LHPP with a genome-wide significant association.

Norepinephrine Transporter Polymorphisms

Attempts to find a correlation between norepinephrine transporter polymorphisms and depression have yielded negative results.

One review identified multiple frequently studied candidate genes. The genes encoding for the 5-HTT and 5-HT2A receptor were inconsistently associated with depression and treatment response. Mixed results were found for brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. Polymorphisms in the tryptophan hydroxylase gene was found to be tentatively associated with suicidal behaviour. A meta analysis of 182 case controlled genetic studies published in 2008 found Apolipoprotein E verepsilon 2 to be protective, and GNB3 825T, MTHFR 677T, SLC6A4 44bp insertion or deletions, and SLC6A3 40 bpVNTR 9/10 genotype to confer risk.

Circadian Rhythm

Depression may be related to abnormalities in the circadian rhythm, or biological clock.

A well synchronised circadian rhythm is critical for maintaining optimal health. Adverse changes and alterations in the circadian rhythm have been associated various neurological disorders and mood disorders including depression.

Sleep

Sleep disturbance is the most prominent symptom in depressive patients. Studies about sleep electroencephalograms have shown characteristic changes in depression such as reductions in non-rapid eye movement sleep production, disruptions of sleep continuity and disinhibition of rapid eye movement (REM) sleep. Rapid eye movement (REM) sleep – the stage in which dreaming occurs – may be quick to arrive and intense in depressed people. REM sleep depends on decreased serotonin levels in the brain stem, and is impaired by compounds, such as antidepressants, that increase serotonergic tone in brain stem structures. Overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation activates serotonergic neurons, leading to processes similar to the therapeutic effect of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Depressed individuals can exhibit a significant lift in mood after a night of sleep deprivation. SSRIs may directly depend on the increase of central serotonergic neurotransmission for their therapeutic effect, the same system that impacts cycles of sleep and wakefulness.

Light Therapy

Research on the effects of light therapy on seasonal affective disorder suggests that light deprivation is related to decreased activity in the serotonergic system and to abnormalities in the sleep cycle, particularly insomnia. Exposure to light also targets the serotonergic system, providing more support for the important role this system may play in depression. Sleep deprivation and light therapy both target the same brain neurotransmitter system and brain areas as antidepressant drugs, and are now used clinically to treat depression. Light therapy, sleep deprivation and sleep time displacement (sleep phase advance therapy) are being used in combination quickly to interrupt a deep depression in people who are hospitalised for MDD.

Increased and decreased sleep length appears to be a risk factor for depression. People with MDD sometimes show diurnal and seasonal variation of symptom severity, even in non-seasonal depression. Diurnal mood improvement was associated with activity of dorsal neural networks. Increased mean core temperature was also observed. One hypothesis proposed that depression was a result of a phase shift.

Daytime light exposure correlates with decreased serotonin transporter activity, which may underlie the seasonality of some depression.

Monoamines

Monoamines are neurotransmitters that include serotonin, dopamine, norepinephrine, and epinephrine.

Illustration of the major elements in a prototypical synapse. Synapses are gaps between nerve cells. These cells convert their electrical impulses into bursts of chemical relayers, called neurotransmitters, which travel across the synapses to receptors on adjacent cells, triggering electrical impulses to travel down the latter cells.

Monoamine Hypothesis of Depression

Many antidepressant drugs acutely increase synaptic levels of the monoamine neurotransmitter, serotonin, but they may also enhance the levels of norepinephrine and dopamine. The observation of this efficacy led to the monoamine hypothesis of depression, which postulates that the deficit of certain neurotransmitters is responsible for depression, and even that certain neurotransmitters are linked to specific symptoms. Normal serotonin levels have been linked to mood and behaviour regulation, sleep, and digestion; norepinephrine to the fight-or-flight response; and dopamine to movement, pleasure, and motivation. Some have also proposed the relationship between monoamines and phenotypes such as serotonin in sleep and suicide, norepinephrine in dysphoria, fatigue, apathy, cognitive dysfunction, and dopamine in loss of motivation and psychomotor symptoms.[31] The main limitation for the monoamine hypothesis of depression is the therapeutic lag between initiation of antidepressant treatment and perceived improvement of symptoms. One explanation for this therapeutic lag is that the initial increase in synaptic serotonin is only temporary, as firing of serotonergic neurons in the dorsal raphe adapt via the activity of 5-HT1A autoreceptors. The therapeutic effect of antidepressants is thought to arise from autoreceptor desensitization over a period of time, eventually elevating firing of serotonergic neurons.

Serotonin

Initial studies of serotonin in depression examined peripheral measures such as the serotonin metabolite 5-Hydroxyindoleacetic acid (5-HIAA) and platelet binding. The results were generally inconsistent, and may not generalise to the central nervous system. However evidence from receptor binding studies and pharmacological challenges provide some evidence for dysfunction of serotonin neurotransmission in depression. Serotonin may indirectly influence mood by altering emotional processing biases that are seen at both the cognitive/behavioural and neural level. Pharmacologically reducing serotonin synthesis, and pharmacologically enhancing synaptic serotonin can produce and attenuate negative affective biases, respectively. These emotional processing biases may explain the therapeutic gap.

Dopamine

While various abnormalities have been observed in dopaminergic systems, results have been inconsistent. People with MDD have an increased reward response to dextroamphetamine compared to controls, and it has been suggested that this results from hypersensitivity of dopaminergic pathways due to natural hypoactivity. While polymorphisms of the D4 and D3 receptor have been implicated in depression, associations have not been consistently replicated. Similar inconsistency has been found in post-mortem studies, but various dopamine receptor agonists show promise in treating MDD. There is some evidence that there is decreased nigrostriatal pathway activity in people with melancholic depression (psychomotor retardation). Further supporting the role of dopamine in depression is the consistent finding of decreased cerebrospinal fluid and jugular metabolites of dopamine, as well as post mortem findings of altered Dopamine receptor D3 and dopamine transporter expression. Studies in rodents have supported a potential mechanism involving stress-induced dysfunction of dopaminergic systems.

Monoamine receptors affect phospholipase C and adenylyl cyclase inside of the cell. Green arrows means stimulation and red arrows inhibition. Serotonin receptors are blue, norepinephrine orange, and dopamine yellow. Phospholipase C and adenylyl cyclase start a signalling cascade which turn on or off genes in the cell. Sufficient ATP from mitochondria is required for these downstream signalling events. The 5HT-3 receptor is associated with gastrointestinal adverse effects and has no relationship to the other monoamine receptors.

Catecholamines

A number of lines of evidence indicative of decreased adrenergic activity in depression have been reported. Findings include the decreased activity of tyrosine hydroxylase, decreased size of the locus coeruleus, increased alpha 2 adrenergic receptor density, and decreased alpha 1 adrenergic receptor density. Furthermore, norepinephrine transporter knockout in mice models increases their tolerance to stress, implicating norepinephrine in depression.

One method used to study the role of monoamines is monoamine depletion. Depletion of tryptophan (the precursor of serotonin), tyrosine and phenylalanine (precursors to dopamine) does result in decreased mood in those with a predisposition to depression, but not in persons lacking the predisposition. On the other hand, inhibition of dopamine and norepinephrine synthesis with alpha-methyl-para-tyrosine does not consistently result in decreased mood.

Monoamine Oxidase

An offshoot of the monoamine hypothesis suggests that monoamine oxidase A (MAO-A), an enzyme which metabolises monoamines, may be overly active in depressed people. This would, in turn, cause the lowered levels of monoamines. This hypothesis received support from a PET study, which found significantly elevated activity of MAO-A in the brain of some depressed people. In genetic studies, the alterations of MAO-A-related genes have not been consistently associated with depression. Contrary to the assumptions of the monoamine hypothesis, lowered but not heightened activity of MAO-A was associated with depressive symptoms in adolescents. This association was observed only in maltreated youth, indicating that both biological (MAO genes) and psychological (maltreatment) factors are important in the development of depressive disorders. In addition, some evidence indicates that disrupted information processing within neural networks, rather than changes in chemical balance, might underlie depression.

Limitations

Since the 1990s, research has uncovered multiple limitations of the monoamine hypothesis, and its inadequacy has been criticised within the psychiatric community. For one thing, serotonin system dysfunction cannot be the sole cause of depression. Not all patients treated with antidepressants show improvements despite the usually rapid increase in synaptic serotonin. If significant mood improvements do occur, this is often not for at least two to four weeks. One possible explanation for this lag is that the neurotransmitter activity enhancement is the result of auto receptor desensitization, which can take weeks. Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in people with MDD. The antidepressants that do not act through the monoamine system, such as tianeptine and opipramol, have been known for a long time. There have also been inconsistent findings with regard to levels of serum 5-HIAA, a metabolite of serotonin. Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people. Another problem that presents is that drugs that deplete monoamines may actually have antidepressant properties. Further, some have argued that depression may be marked by a hyperserotonergic state. Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.

Receptor Binding

As of 2012, efforts to determine differences in neurotransmitter receptor expression or for function in the brains of people with MDD using positron emission tomography (PET) had shown inconsistent results. Using the PET imaging technology and reagents available as of 2012, it appeared that the D1 receptor may be under-expressed in the striatum of people with MDD. 5-HT1A receptor binding literature is inconsistent; however, it leans towards a general decrease in the mesiotemporal cortex. 5-HT2A receptor binding appears to be unregulated in people with MDD. Results from studies on 5-HTT binding are variable, but tend to indicate higher levels in people with MDD. Results with D2/D3 receptor binding studies are too inconsistent to draw any conclusions. Evidence supports increased MAO activity in people with MDD, and it may even be a trait marker (not changed by response to treatment). Muscarinic receptor binding appears to be increased in depression, and, given ligand binding dynamics, suggests increased cholinergic activity.

Four meta analyses on receptor binding in depression have been performed, two on serotonin transporter (5-HTT), one on 5-HT1A, and another on dopamine transporter (DAT). One meta analysis on 5-HTT reported that binding was reduced in the midbrain and amygdala, with the former correlating with greater age, and the latter correlating with depression severity. Another meta-analysis on 5-HTT including both post-mortem and in vivo receptor binding studies reported that while in vivo studies found reduced 5-HTT in the striatum, amygdala and midbrain, post mortem studies found no significant associations. 5-HT1A was found to be reduced in the anterior cingulate cortex, mesiotemporal lobe, insula, and hippocampus, but not in the amygdala or occipital lobe. The most commonly used 5-HT1A ligands are not displaced by endogenous serotonin, indicating that receptor density or affinity is reduced. Dopamine transporter binding is not changed in depression.

Emotional Processing and Neural Circuits

Emotional Bias

People with MDD show a number of biases in emotional processing, such as a tendency to rate happy faces more negatively, and a tendency to allocate more attentional resources to sad expressions. Depressed people also have impaired recognition of happy, angry, disgusted, fearful and surprised, but not sad faces. Functional neuroimaging has demonstrated hyperactivity of various brain regions in response to negative emotional stimuli, and hypoactivity in response to positive stimuli. One meta analysis reported that depressed subjects showed decreased activity in the left dorsolateral prefrontal cortex and increased activity in the amygdala in response to negative stimuli. Another meta analysis reported elevated hippocampus and thalamus activity in a subgroup of depressed subjects who were medication naïve, not elderly, and had no comorbidities. The therapeutic lag of antidepressants has been suggested to be a result of antidepressants modifying emotional processing leading to mood changes. This is supported by the observation that both acute and sub-chronic SSRI administration increases response to positive faces. Antidepressant treatment appears to reverse mood congruent biases in limbic, prefrontal, and fusiform areas. dlPFC response is enhanced and amygdala response is attenuated during processing of negative emotions, the former or which is thought to reflect increased top down regulation. The fusiform gyrus and other visual processing areas respond more strongly to positive stimuli with antidepressant treatment, which is thought to reflect the a positive processing bias. These effects do not appear to be unique to serotonergic or noradrenergic antidepressants, but also occur in other forms of treatment such as deep brain stimulation.

Neural Circuits

One meta analysis of functional neuroimaging in depression observed a pattern of abnormal neural activity hypothesized to reflect an emotional processing bias. Relative to controls, people with MDD showed hyperactivity of circuits in the salience network (SN), composed of the pulvinar nuclei, the insula, and the dorsal anterior cingulate cortex (dACC), as well as decreased activity in regulatory circuits composed of the striatum and dlPFC.

A neuroanatomical model called the limbic-cortical model has been proposed to explain early biological findings in depression. The model attempts to relate specific symptoms of depression to neurological abnormalities. Elevated resting amygdala activity was proposed to underlie rumination, as stimulation of the amygdala has been reported to be associated with the intrusive recall of negative memories. The ACC was divided into pregenual (pgACC) and subgenual regions (sgACC), with the former being electrophysiologically associated with fear, and the latter being metabolically implicated in sadness in healthy subjects. Hyperactivity of the lateral orbitofrontal and insular regions, along with abnormalities in lateral prefrontal regions was suggested to underlie maladaptive emotional responses, given the regions roles in reward learning. This model and another termed “the cortical striatal model”, which focused more on abnormalities in the cortico-basal ganglia-thalamo-cortical loop, have been supported by recent literature. Reduced striatal activity, elevated OFC activity, and elevated sgACC activity were all findings consistent with the proposed models. However, amygdala activity was reported to be decreased, contrary to the limbic-cortical model. Furthermore, only lateral prefrontal regions were modulated by treatment, indicating that prefrontal areas are state markers (i.e. dependent upon mood), while subcortical abnormalities are trait markers (i.e. reflect a susceptibility).

Reward

While depression severity as a whole is not correlated with a blunted neural response to reward, anhedonia is directly correlated to reduced activity in the reward system. The study of reward in depression is limited by heterogeneity in the definition and conceptualisations of reward and anhedonia. Anhedonia is broadly defined as a reduced ability to feel pleasure, but questionnaires and clinical assessments rarely distinguish between motivational “wanting” and consummatory “liking”. While a number of studies suggest that depressed subjects rate positive stimuli less positively and as less arousing, a number of studies fail to find a difference. Furthermore, response to natural rewards such as sucrose does not appear to be attenuated. General affective blunting may explain “anhedonic” symptoms in depression, as meta analysis of both positive and negative stimuli reveal reduced rating of intensity. As anhedonia is a prominent symptom of depression, direct comparison of depressed with healthy subjects reveals increased activation of the subgenual anterior cingulate cortex (sgACC), and reduced activation of the ventral striatum, and in particular the nucleus accumbens (NAcc) in response to positive stimuli. Although the finding of reduced NAcc activity during reward paradigms is fairly consistent, the NAcc is made up of a functionally diverse range of neurons, and reduced blood-oxygen-level dependent (BOLD) signal in this region could indicate a variety of things including reduced afferent activity or reduced inhibitory output. Nevertheless, these regions are important in reward processing, and dysfunction of them in depression is thought to underlie anhedonia. Residual anhedonia that is not well targeted by serotonergic antidepressants is hypothesized to result from inhibition of dopamine release by activation of 5-HT2C receptors in the striatum. The response to reward in the medial orbitofrontal cortex (OFC) is attenuated in depression, while lateral OFC response is enhanced to punishment. The lateral OFC shows sustained response to absence of reward or punishment, and it is thought to be necessary for modifying behaviour in response to changing contingencies. Hypersensitivity in the lOFC may lead to depression by producing a similar effect to learned helplessness in animals.

Elevated response in the sgACC is a consistent finding in neuroimaging studies using a number of paradigms including reward related tasks. Treatment is also associated with attenuated activity in the sgACC, and inhibition of neurons in the rodent homologue of the sgACC, the infralimbic cortex (IL), produces an antidepressant effect. Hyperactivity of the sgACC has been hypothesized to lead to depression via attenuating the somatic response to reward or positive stimuli. Contrary to studies of functional magnetic resonance imaging response in the sgACC during tasks, resting metabolism is reduced in the sgACC. However, this is only apparent when correcting for the prominent reduction in sgACC volume associated with depression; structural abnormalities are evident at a cellular level, as neuropathological studies report reduced sgACC cell markers. The model of depression proposed from these findings by Drevets et al. suggests that reduced sgACC activity results in enhanced sympathetic nervous system activity and blunted HPA axis feedback. Activity in the sgACC may also not be causal in depression, as the authors of one review that examined neuroimaging in depressed subjects during emotional regulation hypothesized that the pattern of elevated sgACC activity reflected increased need to modulate automatic emotional responses in depression. More extensive sgACC and general prefrontal recruitment during positive emotional processing was associated with blunted subcortical response to positive emotions, and subject anhedonia. This was interpreted by the authors to reflect a downregulation of positive emotions by the excessive recruitment of the prefrontal cortex.

Neuroanatomy

While a number of neuroimaging findings are consistently reported in people with major depressive disorder, the heterogeneity of depressed populations presents difficulties interpreting these findings. For example, averaging across populations may hide certain subgroup related findings; while reduced dlPFC activity is reported in depression, a subgroup may present with elevated dlPFC activity. Averaging may also yield statistically significant findings, such as reduced hippocampal volumes, that are actually present in a subgroup of subjects. Due to these issues and others, including the longitudinal consistency of depression, most neural models are likely inapplicable to all depression.

Structural Neuroimaging

Meta analyses performed using seed-based d mapping have reported grey matter reductions in a number of frontal regions. One meta analysis of early onset general depression reported grey matter reductions in the bilateral anterior cingulate cortex (ACC) and dorsomedial prefrontal cortex (dmPFC). One meta analysis on first episode depression observed distinct patterns of grey matter reductions in medication free, and combined populations; medication free depression was associated with reductions in the right dorsolateral prefrontal cortex, right amygdala, and right inferior temporal gyrus; analysis on a combination of medication free and medicated depression found reductions in the left insula, right supplementary motor area, and right middle temporal gyrus. Another review distinguishing medicated and medication free populations, albeit not restricted to people with their first episode of MDD, found reductions in the combined population in the bilateral superior, right middle, and left inferior frontal gyrus, along with the bilateral parahippocampus. Increases in thalamic and ACC grey matter was reported in the medication free and medicated populations respectively. A meta analysis performed using “activation likelihood estimate” reported reductions in the paracingulate cortex, dACC and amygdala.

Using statistical parametric mapping, one meta analysis replicated previous findings of reduced grey matter in the ACC, medial prefrontal cortex, inferior frontal gyrus, hippocampus and thalamus; however reductions in the OFC and ventromedial prefrontal cortex grey matter were also reported.

Two studies on depression from the ENIGMA consortium have been published, one on cortical thickness, and the other on subcortical volume. Reduced cortical thickness was reported in the bilateral OFC, ACC, insula, middle temporal gyri, fusiform gyri, and posterior cingulate cortices, while surface area deficits were found in medial occipital, inferior parietal, orbitofrontal and precentral regions. Subcortical abnormalities, including reductions in hippocampus and amygdala volumes, which were especially pronounced in early onset depression.

Multiple meta analysis have been performed on studies assessing white matter integrity using fractional anisotropy (FA). Reduced FA has been reported in the corpus callosum (CC) in both first episode medication naïve, and general major depressive populations. The extent of CC reductions differs from study to study. People with MDD who have not taken antidepressants before have been reported to have reductions only in the body of the CC and only in the genu of the CC. On the other hand, general MDD samples have been reported to have reductions in the body of the CC, the body and genu of the CC, and only the genu of the CC. Reductions of FA have also been reported in the anterior limb of the internal capsule (ALIC) and superior longitudinal fasciculus.

Functional Neuroimaging

Studies of resting state activity have utilised a number of indicators of resting state activity, including regional homogeneity (ReHO), amplitude of low frequency fluctuations (ALFF), fractional amplitude of low frequency fluctuations (fALFF), arterial spin labelling (ASL), and positron emission tomography measures of regional cerebral blood flow or metabolism.

MDD is associated with reduced FA in the ALIC and genu/body of the CC.

Studies using ALFF and fALFF have reported elevations in ACC activity, with the former primarily reporting more ventral findings, and the latter more dorsal findings. A conjunction analysis of ALFF and CBF studies converged on the left insula, with previously untreated people having increased insula activity. Elevated caudate CBF was also reported A meta analysis combining multiple indicators of resting activity reported elevated anterior cingulate, striatal, and thalamic activity and reduced left insula, post-central gyrus and fusiform gyrus activity. An activation likelihood estimate (ALE) meta analysis of PET/SPECT resting state studies reported reduced activity in the left insula, pregenual and dorsal anterior cingulate cortex and elevated activity in the thalamus, caudate, anterior hippocampus and amygdala. Compared to the ALE meta analysis of PET/SPECT studies, a study using multi-kernel density analysis reported hyperactivity only in the pulvinar nuclei of the thalamus.

Brain Regions

Research on the brains of people with MDD usually shows disturbed patterns of interaction between multiple parts of the brain. Several areas of the brain are implicated in studies seeking to more fully understand the biology of depression:

Subgenual Cingulate

Studies have shown that Brodmann area 25, also known as subgenual cingulate, is metabolically overactive in treatment-resistant depression. This region is extremely rich in serotonin transporters and is considered as a governor for a vast network involving areas like hypothalamus and brain stem, which influences changes in appetite and sleep; the amygdala and insula, which affect the mood and anxiety; the hippocampus, which plays an important role in memory formation; and some parts of the frontal cortex responsible for self-esteem. Thus disturbances in this area or a smaller than normal size of this area contributes to depression. Deep brain stimulation has been targeted to this region in order to reduce its activity in people with treatment resistant depression.

Prefrontal Cortex

One review reported hypoactivity in the prefrontal cortex of those with depression compared to controls. The prefrontal cortex is involved in emotional processing and regulation, and dysfunction of this process may be involved in the aetiology of depression. One study on antidepressant treatment found an increase in PFC activity in response to administration of antidepressants. One meta analysis published in 2012 found that areas of the prefrontal cortex were hypoactive in response to negative stimuli in people with MDD. One study suggested that areas of the prefrontal cortex are part of a network of regions including dorsal and pregenual cingulate, bilateral middle frontal gyrus, insula and superior temporal gyrus that appear to be hypoactive in people with MDD. However the authors cautioned that the exclusion criteria, lack of consistency and small samples limit results.

Amygdala

The amygdala, a structure involved in emotional processing appears to be hyperactive in those with major depressive disorder. The amygdala in unmedicated depressed persons tended to be smaller than in those that were medicated, however aggregate data shows no difference between depressed and healthy persons. During emotional processing tasks right amygdala is more active than the left, however there is no differences during cognitive tasks, and at rest only the left amygdala appears to be more hyperactive. One study, however, found no difference in amygdala activity during emotional processing tasks.

Hippocampus

Atrophy of the hippocampus has been observed during depression, consistent with animal models of stress and neurogenesis.

Stress can cause depression and depression-like symptoms through monoaminergic changes in several key brain regions as well as suppression in hippocampal neurogenesis. This leads to alteration in emotion and cognition related brain regions as well as HPA axis dysfunction. Through the dysfunction, the effects of stress can be exacerbated including its effects on 5-HT. Furthermore, some of these effects are reversed by antidepressant action, which may act by increasing hippocampal neurogenesis. This leads to a restoration in HPA activity and stress reactivity, thus restoring the deleterious effects induced by stress on 5-HT.

The hypothalamic-pituitary-adrenal axis is a chain of endocrine structures that are activated during the body’s response to stressors of various sorts. The HPA axis involves three structure, the hypothalamus which release CRH that stimulates the pituitary gland to release ACTH which stimulates the adrenal glands to release cortisol. Cortisol has a negative feedback effect on the pituitary gland and hypothalamus. In people with MDD this often shows increased activation in depressed people, but the mechanism behind this is not yet known. Increased basal cortisol levels and abnormal response to dexamethasone challenges have been observed in people with MDD. Early life stress has been hypothesized as a potential cause of HPA dysfunction. HPA axis regulation may be examined through a dexamethasone suppression tests, which tests the feedback mechanisms. Non-suppression of dexamethasone is a common finding in depression, but is not consistent enough to be used as a diagnostic tool. HPA axis changes may be responsible for some of the changes such as decreased bone mineral density and increased weight found in people with MDD. One drug, ketoconazole, currently under development has shown promise in treating MDD.

Hippocampal Neurogenesis

Reduced hippocampal neurogenesis leads to a reduction in hippocampal volume. A genetically smaller hippocampus has been linked to a reduced ability to process psychological trauma and external stress, and subsequent predisposition to psychological illness. Depression without familial risk or childhood trauma has been linked to a normal hippocampal volume but localised dysfunction.

Animal Models

A number of animal models exist for depression, but they are limited in that depression involves primarily subjective emotional changes. However, some of these changes are reflected in physiology and behaviour, the latter of which is the target of many animal models. These models are generally assessed according to four facets of validity; the reflection of the core symptoms in the model; the predictive validity of the model; the validity of the model with regard to human characteristics of aetiology; and the biological plausibility.

Different models for inducing depressive behaviours have been utilised; neuroanatomical manipulations such as olfactory bulbectomy or circuit specific manipulations with optogenetics; genetic models such as 5-HT1A knockout or selectively bred animals; models involving environmental manipulation associated with depression in humans, including chronic mild stress, early life stress and learned helplessness. The validity of these models in producing depressive behaviours may be assessed with a number of behavioural tests. Anhedonia and motivational deficits may, for example, be assessed via examining an animal’s level of engagement with rewarding stimuli such as sucrose or intracranial self-stimulation. Anxious and irritable symptoms may be assessed with exploratory behaviour in the presence of a stressful or novelty environment, such as the open field test, novelty suppressed feeding, or the elevated plus-maze. Fatigue, psychomotor poverty, and agitation may be assessed with locomotor activity, grooming activity, and open field tests.

Animal models possess a number of limitations due to the nature of depression. Some core symptoms of depression, such as rumination, low self-esteem, guilt, and depressed mood cannot be assessed in animals as they require subjective reporting. From an evolutionary standpoint, the behaviour correlates of defeats of loss are thought to be an adaptive response to prevent further loss. Therefore, attempts to model depression that seeks to induce defeat or despair may actually reflect adaption and not disease. Furthermore, while depression and anxiety are frequently comorbid, dissociation of the two in animal models is difficult to achieve. Pharmacological assessment of validity is frequently disconnected from clinical pharmacotherapeutics in that most screening tests assess acute effects, while antidepressants normally take a few weeks to work in humans.

Neurocircuits

Regions involved in reward are common targets of manipulation in animal models of depression, including the nucleus accumbens (NAc), ventral tegmental area (VTA), ventral pallidum (VP), lateral habenula (LHb) and medial prefrontal cortex (mPFC). Tentative fMRI studies in humans demonstrate elevated LHb activity in depression. The lateral habenula projects to the RMTg to drive inhibition of dopamine neurons in the VTA during omission of reward. In animal models of depression, elevated activity has been reported in LHb neurons that project to the ventral tegmental area (ostensibly reducing dopamine release). The LHb also projects to aversion reactive mPFC neurons, which may provide an indirect mechanism for producing depressive behaviours. Learned helplessness induced potentiation of LHb synapses are reversed by antidepressant treatment, providing predictive validity. A number of inputs to the LHb have been implicated in producing depressive behaviours. Silencing GABAergic projections from the NAc to the LHb reduces conditioned place preference induced in social aggression, and activation of these terminals induces CPP. Ventral pallidum firing is also elevated by stress induced depression, an effect that is pharmacologically valid, and silencing of these neurons alleviates behavioural correlates of depression. Tentative in vivo evidence from people with MDD suggests abnormalities in dopamine signalling. This led to early studies investigating VTA activity and manipulations in animal models of depression. Massive destruction of VTA neurons enhances depressive behaviours, while VTA neurons reduce firing in response to chronic stress. However, more recent specific manipulations of the VTA produce varying results, with the specific animal model, duration of VTA manipulation, method of VTA manipulation, and subregion of VTA manipulation all potentially leading to differential outcomes. Stress and social defeat induced depressive symptoms, including anhedonia, are associated with potentiation of excitatory inputs to Dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) and depression of excitatory inputs to Dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs). Optogenetic excitation of D1-MSNs alleviates depressive symptoms and is rewarding, while the same with D2-MSNs enhances depressive symptoms. Excitation of glutaminergic inputs from the ventral hippocampus reduces social interactions, and enhancing these projections produces susceptibility to stress-induced depression. Manipulations of different regions of the mPFC can produce and attenuate depressive behaviours. For example, inhibiting mPFC neurons specifically in the intralimbic cortex attenuates depressive behaviours. The conflicting findings associated with mPFC stimulation, when compared to the relatively specific findings in the infralimbic cortex, suggest that the prelimbic cortex and infralimbic cortex may mediate opposing effects. mPFC projections to the raphe nuclei are largely GABAergic and inhibit the firing of serotonergic neurons. Specific activation of these regions reduce immobility in the forced swim test but do not affect open field or forced swim behaviour. Inhibition of the raphe shifts the behavioural phenotype of uncontrolled stress to a phenotype closer to that of controlled stress.

Altered Neuroplasticity

Recent studies have called attention to the role of altered neuroplasticity in depression. A review found a convergence of three phenomena:

Chronic stress reduces synaptic and dendritic plasticity;
Depressed subjects show evidence of impaired neuroplasticity (e.g. shortening and reduced complexity of dendritic trees); and
Anti-depressant medications may enhance neuroplasticity at both a molecular and dendritic level.

The conclusion is that disrupted neuroplasticity is an underlying feature of depression, and is reversed by antidepressants.

Blood levels of BDNF in people with MDD increase significantly with antidepressant treatment and correlate with decrease in symptoms. Post mortem studies and rat models demonstrate decreased neuronal density in the prefrontal cortex thickness in people with MDD. Rat models demonstrate histological changes consistent with MRI findings in humans, however studies on neurogenesis in humans are limited. Antidepressants appear to reverse the changes in neurogenesis in both animal models and humans.

Inflammation

Various reviews have found that general inflammation may play a role in depression. One meta analysis of cytokines in people with MDD found increased levels of pro-inflammatory IL-6 and TNF-a levels relative to controls. The first theories came about when it was noticed that interferon therapy caused depression in a large number of people receiving it. Meta analysis on cytokine levels in people with MDD have demonstrated increased levels of IL-1, IL-6, C-reactive protein, but not IL-10. Increased numbers of T-Cells presenting activation markers, levels of neopterin, IFN gamma, sTNFR, and IL-2 receptors have been observed in depression. Various sources of inflammation in depressive illness have been hypothesized and include trauma, sleep problems, diet, smoking and obesity. Cytokines, by manipulating neurotransmitters, are involved in the generation of sickness behaviour, which shares some overlap with the symptoms of depression. Neurotransmitters hypothesized to be affected include dopamine and serotonin, which are common targets for antidepressant drugs. Induction of indolamine-2,3 dioxygenease by cytokines has been proposed as a mechanism by which immune dysfunction causes depression. One review found normalization of cytokine levels after successful treatment of depression. A meta analysis published in 2014 found the use of anti-inflammatory drugs such as NSAIDs and investigational cytokine inhibitors reduced depressive symptoms. Exercise can act as a stressor, decreasing the levels of IL-6 and TNF-a and increasing those of IL-10, an anti-inflammatory cytokine.

Inflammation is also intimately linked with metabolic processes in humans. For example, low levels of Vitamin D have been associated with greater risk for depression. The role of metabolic biomarkers in depression is an active research area. Recent work has explored the potential relationship between plasma sterols and depressive symptom severity.

Oxidative Stress

A marker of DNA oxidation, 8-Oxo-2′-deoxyguanosine, has been found to be increased in both the plasma and urine of people with MDD. This along with the finding of increased F2-isoprostanes levels found in blood, urine and cerebrospinal fluid indicate increased damage to lipids and DNA in people with MDD. Studies with 8-Oxo-2′ Deoxyguanosine varied by methods of measurement and type of depression, but F2-Isoprostane level was consistent across depression types. Authors suggested lifestyle factors, dysregulation of the HPA axis, immune system and autonomics nervous system as possible causes. Another meta-analysis found similar results with regards to oxidative damage products as well as decreased oxidative capacity. Oxidative DNA damage may play a role in MDD.

Mitochondrial Dysfunction:

Increased markers of oxidative stress relative to controls have been found in people with MDD. These markers include high levels of RNS and ROS which have been shown to influence chronic inflammation, damaging the electron transport chain and biochemical cascades in mitochondria. This lowers the activity of enzymes in the respiratory chain resulting in mitochondrial dysfunction. The brain is a highly energy-consuming and has little capacity to store glucose as glycogen and so depends greatly on mitochondria. Mitochondrial dysfunction has been linked to the dampened neuroplasticity observed in depressed brains.

Large-Scale Brain Network Theory

Instead of studying one brain region, studying large scale brain networks is another approach to understanding psychiatric and neurological disorders, supported by recent research that has shown that multiple brain regions are involved in these disorders. Understanding the disruptions in these networks may provide important insights into interventions for treating these disorders. Recent work suggests that at least three large-scale brain networks are important in psychopathology.

Central Executive Network

The central executive network is made up of fronto-parietal regions, including dorsolateral prefrontal cortex and lateral posterior parietal cortex. This network is involved in high level cognitive functions such as maintaining and using information in working memory, problem solving, and decision making. Deficiencies in this network are common in most major psychiatric and neurological disorders, including depression. Because this network is crucial for everyday life activities, those who are depressed can show impairment in basic activities like test taking and being decisive.

Default Mode Network

The default mode network includes hubs in the prefrontal cortex and posterior cingulate, with other prominent regions of the network in the medial temporal lobe and angular gyrus. The default mode network is usually active during mind-wandering and thinking about social situations. In contrast, during specific tasks probed in cognitive science (for example, simple attention tasks), the default network is often deactivated. Research has shown that regions in the default mode network (including medial prefrontal cortex and posterior cingulate) show greater activity when depressed participants ruminate (that is, when they engage in repetitive self-focused thinking) than when typical, healthy participants ruminate. People with MDD also show increased connectivity between the default mode network and the subgenual cingulate and the adjoining ventromedial prefrontal cortex in comparison to healthy individuals, individuals with dementia or with autism. Numerous studies suggest that the subgenual cingulate plays an important role in the dysfunction that characterizes major depression. The increased activation in the default mode network during rumination and the atypical connectivity between core default mode regions and the subgenual cingulate may underlie the tendency for depressed individual to get “stuck” in the negative, self-focused thoughts that often characterise depression. However, further research is needed to gain a precise understanding of how these network interactions map to specific symptoms of depression.

Salience Network

The salience network is a cingulate-frontal operculum network that includes core nodes in the anterior cingulate and anterior insula. A salience network is a large-scale brain network involved in detecting and orienting the most pertinent of the external stimuli and internal events being presented. Individuals who have a tendency to experience negative emotional states (scoring high on measures of neuroticism) show an increase in the right anterior insula during decision-making, even if the decision has already been made. This atypically high activity in the right anterior insula is thought to contribute to the experience of negative and worrisome feelings. In MDD, anxiety is often a part of the emotional state that characterises depression.

An Overview of the Biology of Bipolar Disorder

Published on 01/02/2022 by Andrew Marshall2 Comments

Introduction

Bipolar disorder is an affective disorder characterised by periods of elevated and depressed mood.

The cause and mechanism of bipolar disorder is not yet known, and the study of its biological origins is ongoing. Although no single gene causes the disorder, a number of genes are linked to increase risk of the disorder, and various gene environment interactions may play a role in predisposing individuals to developing bipolar disorder. Neuroimaging and post-mortem studies have found abnormalities in a variety of brain regions, and most commonly implicated regions include the ventral prefrontal cortex and amygdala. Dysfunction in emotional circuits located in these regions have been hypothesized as a mechanism for bipolar disorder. A number of lines of evidence suggests abnormalities in neurotransmission, intracellular signalling, and cellular functioning as possibly playing a role in bipolar disorder.

Studies of bipolar disorder, particularly neuroimaging studies, are vulnerable to the confounding effects such as medication, comorbidity, and small sample size, leading to underpowered independent studies, and significant heterogeneity.

Brain imaging studies have revealed differences in the volume of various brain regions between patients with bipolar disorder and healthy control subjects.

Aetiology

Genetic

The etiology of bipolar disorder is unknown. The overall heritability of bipolar is estimated at 79%-93%, and first degree relatives of bipolar probands have a relative risk of developing bipolar around 7-10. While the heritability is high, no specific genes have been conclusively associated with bipolar, and a number of hypothesis have been posited to explain this fact. “The polygenic common rare variant” hypothesis suggests that a large number of risk conferring genes are carried in a population, and that a disease manifests when a person has a sufficient number of these genes. The “multiple rare variant” model suggests that multiple genes that are rare in the population are capable of causing a disease, and that carrying one or a few can lead to disease. The familial transmission of mania and depression are largely independent of each other. This raises the possibility that bipolar is actually two biologically distinct but highly comorbid conditions.

A number of genome wide associations have been reported, including CACNA1C and ODZ4, and TRANK1. Less consistently reported loci include ANK3 and NCAN, ITIH1, ITIH3 and NEK4. Significant overlaps with schizophrenia have been reported at CACNA1C, ITIH, ANK3, and ZNF804A. This overlap is congruent with the observation that relatives of probands with schizophrenia are at higher risk for bipolar disorder and vice versa.

In light of associations between bipolar and circadian abnormalities (such as decreased need for sleep and increased sleep latency), polymorphisms in the CLOCK gene have been tested for association, although findings have been inconsistent, and one meta analysis has reported no association with either bipolar or major depressive disorder. Other circadian genes associated with bipolar at relaxed significance thresholds include ARTNL, RORB, and DEC1. One meta analysis reported a significant association of the short allele of the serotonin transporter, although the study was specific to European populations. Two polymorphisms in the tryptophan hydroxylase 2 gene have been associated with bipolar disorder. NFIA has been linked with seasonal patterns of mania.

One particular SNP located on CACNA1C that confers risk for bipolar disorder is also associated with elevated CACNA1C mRNA expression in the prefrontal cortex, and increased calcium channel expression in neurons made from patient induced pluripotent stem cells.

No significant association exists for the BDNF Val66Met allele and bipolar disorder, except possibly in a subgroup of bipolar II cases, and suicide.

Due to the inconsistent findings in GWAS, multiple studies have undertaken the approach of analysing SNPs in biological pathways. Signalling pathways traditionally associated with bipolar disorder that have been supported by these studies include CRH signalling, cardiac β-adrenergic signalling, phospholipase C signalling, glutamate receptor signalling, cardiac hypertrophy signalling, Wnt signalling, notch signalling, and endothelin 1 signalling. Of the 16 genes identified in these pathways, three were found to be dysregulated in the dorsolateral prefrontal cortex portion of the brain in post-mortem studies, CACNA1C, GNG2, and ITPR2.

Advanced paternal age has been linked to a somewhat increased chance of bipolar disorder in offspring, consistent with a hypothesis of increased new genetic mutations.

A meta-analysis was performed to determine the association between bipolar disorder and oxidative DNA damage measured by 8-hydroxy-2′-8-deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG). Levels of 8-OHdG and 8-oxodG are widely used as measures of oxidative stress in mental illnesses. It was determined from this meta-analysis that oxidative DNA damage was significantly increased in bipolar disorder.

Environmental

Manic episodes can be produced by sleep deprivation in around 30% of people with bipolar. While not all people with bipolar demonstrate seasonality of affective symptoms, it is a consistently reported feature that supports theories of circadian dysfunction in bipolar.

Risk factors for bipolar include obstetric complications, abuse, drug use, and major life stressors.

The “kindling model” of mood disorders suggests that major environmental stressors trigger initial mood episodes, but as mood episodes occur, weaker and weaker triggers can precipitate an affective episode. This model was initially created for epilepsy, to explain why weaker and weaker electrical stimulation was necessary to elicit a seizure as the disease progressed. While parallels have been drawn between bipolar disorder and epilepsy, supporting the kindling hypothesis, this model is generally not supported by studies directly assessing it in bipolar subjects.

Neurological Disorders

Mania occurs secondary to neurological conditions between a rate of 2% to 30%. Mania is most commonly seen in right sided lesions, lesions that disconnect the prefrontal cortex, or excitatory lesions in the left hemisphere.

Diseases associated with “secondary mania” include Cushing’s disease, dementia, delirium, meningitis, hyperparathyroidism, hypoparathyroidism, thyrotoxicosis, multiple sclerosis, Huntington’s disease, epilepsy, neurosyphilis, HIV dementia, uraemia, as well as traumatic brain injury and vitamin B12 deficiency.

Pathophysiology

Neurobiological and Neuroanatomical Models

The main loci of neuroimaging and neuropathological findings in bipolar have been proposed to constitute dysfunction in a “visceromotor” network, composed of the mPFC, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), hippocampus, amygdala, hypothalamus, striatum and thalamus.

A model of functional neuroanatomy produced by a workgroup led by Stephen M. Strakowski concluded that bipolar was characterized by reduced connectivity, due to abnormal pruning or development, in the prefrontal-striatal-pallidal-thalamic-limbic network leading to dysregulated emotional responses. This model was supported by a number of common neuroimaging findings. Dysregulation of limbic structures is evinced by the fact that hyperactivity in the amygdala in response to facial stimuli has been consistently reported in mania. While amygdala hyperactivity is not a uniform finding, a number of methodological challenges could explain discrepancies. As most studies utilize fMRI to measure blood-oxygen-level dependent signal, excess baseline activity could result in null findings due to subtraction analysis. Furthermore, heterogenous study design could mask consistent hyperactivity to specific stimuli. Regardless of directionality of amygdala abnormalities, as the amygdala plays a central role in emotional systems, these findings support dysfunctional emotional circuits in bipolar. A general reduction in ventrolateral prefrontal cortex activity is observed in bipolar, and is lateralised with regard to mood (i.e. left-depression, right-mania), and may underlie amygdala abnormalities. The dorsal ACC is commonly under-activated in bipolar, and is generally implicated in cognitive functions, while the ventral ACC is hyperactived and implicated in emotional functions. Combined, these abnormalities support the prefrontal-striatal-pallidial-thalamic limbic network underlying dysfunction in emotional regulation in bipolar disorder. Strakowski, along with DelBello and Adler have put forward a model of “anterior limbic” dysfunction in bipolar disorder in a number of papers.

In 2007, Green and colleagues suggested a model of bipolar disorder based on the convergence of cognitive and emotional processing on certain structures. For example, the dACC and sgACC were cognitively associated with impairment of inhibition of emotional responses and self monitoring, which could translate to emotional stimuli having excessive impact on mood. Deficits in working memory associated with abnormal dlPFC function could also translate to impaired ability to represent emotional stimuli, and therefore the impaired ability to reappraise emotional stimuli. Dysfunction in the amygdala and striatum has been associated with attentional biases, and may represent a bottom up mechanism of dysfunctional emotional processing.

Blond et al. proposed a model centred on dysfunction in an “amygdala-anterior paralimbic” system. This model was based on the consistent functional and structural abnormalities in the ventral prefrontal cortex and amygdala. The model also proposes a developmental component of bipolar disorder, wherein limbic abnormalities are present early on, but rostral prefrontal abnormalities develop later in the course. The importance of limbic dysfunction early in development is highlighted by the observation that amygdala lesions early in adulthood produce emotional abnormalities that are not present in people who develop amygdala damage in adulthood.

Lateralised seizure sequelae similar to bipolar has been reported in people with mesial temporal lobe seizures, and provides support for kindling hypotheses about bipolar. This observation led to the first experiments with anticonvulsants in bipolar, which are effective in stabilising mood. Studies reporting reduced markers of inhibitory interneurons post-mortem link the analogy with epilepsy to a possible reduction in inhibitory activity in emotional circuits. Overlap with epilepsy extends to include abnormalities in intracellular signalling, biochemistry in the hippocampus and prefrontal cortex, and structure and function of the amygdala.

The phenomenology and neuroanatomy of mania secondary to neurological disorders is consistent with findings in primary mania and bipolar disorder. While the diversity of lesions and difficulty in ruling out premorbid psychiatric conditions limit the conclusions that can be drawn, a number of findings are fairly consistent. Structurally, secondary mania is associated with destructive lesions that tend to occur in the right hemisphere, particularly the frontal cortex, mesial temporal lobe and basal ganglia. Functionally hyperactivity in the left basal ganglia and subcortical structures, and hypoactivity in the right ventral prefrontal and basotemporal cortex have been reported in cases of secondary mania. The destruction of right hemisphere or frontal areas is hypothesized to lead to a shift to excessive left sided or subcortical reward processing.

John O. Brooks III put forward a model of bipolar disorder involving dysregulation of a circuit called the “corticolimbic system”. The model was based on more or less consistent observations of reduced activity in the mOFC, vlPFC, and dlPFC, as well as the more or less consistent observations of increased activity in the amygdala, parahippocampal gyrus, cerebellar vermis, anterior temporal cortex, sgACC, and ACC. This pattern of abnormal activity was suggested to contribute to disrupted cognitive and affective processes in bipolar disorder.

Neurocognition

During acute mood episodes, people with bipolar demonstrate mood congruent processing biases. Depressed patients are quicker to react to negatively valenced stimuli, while manic patients are quicker to react to positively valenced stimuli. Acute mood episodes are also associated with congruent abnormalities during decision making tasks. Depressed bipolar is associated with conservative responding, while manic bipolar is associated with liberal responses. Both depression and mania are associated with similar and broad cognitive impairments, including on tests of attention, processing speed, working memory, executive functions, and reaction time.

Clinically, mania is characterised by spending sprees, poor judgement, and inappropriate speech and behaviour. Congruent with this, mania is associated impulsivity on Go-No Go tasks, deficits in emotional decision making, poor probabilistic reasoning, impaired ability on continuous performance tasks, set shifting, and planning. The clinical phenomenology and neurocognitive deficits are similar to those seen in patients with damage to the orbitofrontal cortex (OFC), which has been reported in functional neuroimaging studies to be abnormal in bipolar mania. Specifically, reduced blood flow to the lateral OFC has been reported, and may reflect dysfunction that leads to the neurocognitive deficits.

In novel environments, both bipolar manic and bipolar euthymic people demonstrate increased activity, exploration and linear movement that is greater than controls, people with ADHD and people with schizophrenia. Using this behavioural pattern in “reverse translational” studies, this behavioural abnormality has been associated with the cholinergic-aminergic hypothesis, which postulates elevated dopaminergic signalling in mania. Reducing the function of DAT using pharmacological or genetic means produces a similar behavioural pattern in animal models. Pharmacological data is consistent with dysfunction of dopamine in bipolar as some studies have reported hypersensitivity to stimulants (however, some studies have found that stimulants effectively attenuate manic behaviour, and co-morbid ADHD and bipolar are effectively treated with stimulants), and the mechanism of antimanic drugs may involve attenuating dopamine signalling.

Hypersensitivity of reward systems is consistent across mood states in bipolar, and is evident in the prodrome. Increases in goal directed behaviour, risk taking, positive emotions in response to reward, ambitious goal setting and inflexibility in goal directed behaviours are present in euthymia. Neuroimaging studies are consistent with trait hypersensitivity in reward systems, as both mania and depression is associated with elevated resting activity in the striatum, and elevated activity in the striatum and OFC during emotional processing, receipt of reward, and anticipation of reward. Increased activity in the striatum and OFC has also been reported in euthymia during anticipation and receipt of reward, although this finding is extremely inconsistent. These abnormalities may be related to circadian rhythm dysfunction in bipolar, including increased sleep latency, evening preference and poor sleep quality, as the neural systems responsible for both processes are functionally linked. A few lines of evidence suggest that elevated dopamine signalling, possibly due to reduced functionality in DAT, underlie abnormalities in reward function. Dopaminergic drugs such as L-DOPA can precipitate mania, and drugs that attenuate dopaminergic signalling extracellularly (antipsychotics) and intracellularly (lithium) can be efficacious in treating mania. While a large body of translational evidence exists to support DAT hypofunction, in vivo evidence is limited to one study reporting reduced DAT binding in the caudate.

Neuroimaging

Structural

In a review of structural neuroimaging in bipolar disorder, Strakowski proposed dysfunction in an iterative emotional network called the “anterior limbic network”, composed of the thalamus, globus pallidus, striatum, vlPFC, vmPFC, ACC, amygdala, dlPFC, and cerebellar vermis. Structural imaging studies frequently find abnormalities in these regions which are putatively involved in emotional and cognitive functions that are disrupted in bipolar disorder. For example, while structural neuroimaging studies do not always find abnormal PFC volume in bipolar disorder, when they do, PFC volume is reduced. Furthermore, reduced PFC volume is associated with response inhibition deficits and duration of illness. When the PFC at large is not examined and the focus is narrowed to the OFC/vPFC, results more consistently observed reductions, although not in bipolar youth. The sgACC volume is observed to be reduced not only in bipolar disorder, but also in unipolar disorder, as well as people with a family history of affective disorders. Enlargement of the striatum and globus pallidus are commonly found, and although some studies fail to observe this, at least one study has reported no volumetric but subtle morphometric abnormalities.

Structural neuroimaging studies consistently report increased frequency of white matter hyperintensities in people with bipolar. However, whether or not the lesions play a causative role is unknown. It is possible that they are a result of secondary factors, such as the processes underlying an increased risk of cardiovascular disease in bipolar. On the other hand, the observation of reduced white matter integrity in frontal-subcortical regions makes it possible that these hyperintensities play a role dysfunction between limbic and cortical regions. Global brain volume and morphology are normal in bipolar. Regional deficits in volume have been reported in ventrolateral and dorsolateral prefrontal regions. Based on this, it has been suggested that reduced limbic regulation by prefrontal regions plays a role in bipolar. Findings related to the volume of the basal ganglia have been inconsistent.

In healthy controls, amygdala volume is inversely related to age. This relationship is reversed in bipolar disorder, and meta analyses have found reduced amygdala volume in paediatric bipolar disorder, and increased amygdala volume in adulthood. This is hypothesized to reflect abnormal development of amygdala, possibly involving impaired synaptic pruning, although this may reflect medication or compensatory effects; that is, these abnormalities may not be involved in the mechanism of bipolar, and may instead be a consequence.

A 2016 meta analysis reported that bipolar disorder was associated with grey matter reductions bilaterally in the ACC, vmPFC, and insula extending to the temporal lobe. When compared with grey matter reductions in unipolar depression, significant overlap occurred in the insular and medial prefrontal regions. Although unipolar depression was associated with reductions in the ventral most and dorsal most regions of the mPFC and bipolar with a region near the genu of the corpus callosum, the overlap was still statistically significant. Similar to the overlap with major depression, a significant overlap of bipolar disorder with schizophrenia in grey matter volume reduction occurs in the anterior cingulate cortex, medial prefrontal cortex, lateral prefrontal cortex and bilateral insula.

A 2010 meta analysis of differences in regional grey matter volume between controls and bipolar disorder reported reductions bilaterally in the inferior frontal cortex and insula, which extended more prominently in the right side to include the precentral gyrus, as well as grey matter reductions in the pregenual anterior cingulate cortex (BA24) and anterior cingulate cortex (BA32). One meta analysis reported enlargement of the lateral ventricles and globus pallidus, as well as reductions in hippocampus volume and cross sectional area of the corpus callosum. Another meta analysis reported a similar increase volumes of the globus pallidus and lateral ventricles, as well as increased amygdala volume relative to people with schizophrenia. Reductions have also been reported in the right inferior frontal gyrus, insula, pars triangularis, pars opercularis, and middle and superior temporal gyrus. Structural neuroimaging in people who are susceptible to bipolar disorder (i.e. have a number of relatives with bipolar disorder) have produced few consistent results. Consistent abnormalities in adult first degree relatives include larger insular cortex volumes, while offspring demonstrate increased right inferior frontal gyrus volumes.

The ENIGMA bipolar disorder working group reported cortical thinning in the left Pars opercularis (BA44-inferior frontal gyrus), left fusiform gyrus, left rostral middle frontal cortex, right inferior parietal cortex, along with an increase in the right entorhinal cortex. Duration of illness was associated with reductions bilaterally in the pericalcarine gyrus, left rostral anterior cingulate and right cuneus, along with increases in the right entorhinal cortex. Treatment with lithium was associated with increased cortical thickness bilaterally in the superior parietal gyrus, left paracentral gyrus, and left paracentral lobule. A history of psychosis was associated with reduced surface area in the right frontal pole. Another study on subcortical abnormalities by the same research group reported reductions in the hippocampus, amygdala, and thalamus, along with ventricular enlargement.

One meta analysis reported that when correcting for lithium treatment, which was associated with increased hippocampal volume, people with bipolar demonstrate reduced hippocampus volume.

White matter is reduced in the posterior corpus callosum, regions adjacent to the anterior cingulate, the left optic radiation, and right superior longitudinal tract, and increased in the cerebellum and lentiform nuclei.

Functional

Studies examining resting blood flow, or metabolism generally observed abnormalities dependent upon mood state. Bipolar depression is generally associated with dlPFC and mOFC hypometabolism. Less consistent associations include reduced temporal cortex metabolism, increased limbic metabolism and reduced ACC metabolism. Mania is also associated with dlPFC and OFC hypometabolism. Limbic hypermetabolism is more consistent than in bipolar depression, but the overall study quality is low due to limitations associated with neuroimaging in acutely manic patients. Another review reported that mania is generally associated with frontal/ventral hypoactivation, while depression is generally associated with the opposite. A degree of lateralization with regard to abnormalities has been reported, with mania being associated with the right hemisphere, and depression the left. Trait abnormalities in euthymic patients have been observed, including hypoactivity in the ventral prefrontal cortex, and hyperactivity in the amygdala.

During cognitive or emotional tasks, functional neuroimaging studies, consistently find hyperactivation of the basal ganglia, amygdala, and thalamus. Prefrontal abnormalities are less consistently reported, although hyperactivation in the ventral prefrontal cortex is a fairly consistent finding. Hyperactivity in the amygdala and hypoactivity in the medial and ventral prefrontal cortex during exposure to emotional stimuli has been interpreted as reflecting dysfunction in emotional regulation circuits. Increased effective connectivity between the amygdala and orbitofrontal cortex, and elevated striatal responsiveness during reward tasks have been interpreted as hyper-responsiveness in positive emotion and reward circuitry. The abnormal activity in these circuits has been observed in non-emotional tasks, and is congruent with changes in grey and white matter in these circuits. Neural response during reward tasks differentiates unipolar depression from bipolar depression, with the former being associated with reduced neural response and the latter being associated with elevated neural response. An ALE meta analysis of functional neuroimaging comparing adults and adolescents found a larger degree of hyperactivity in the inferior frontal gyrus and precuneus, as well as a larger degree of hypoactivity in the anterior cingulate cortex in adolescents relative to adults.

Regardless of mood state, during response inhibition tasks, people with bipolar disorder underactivate the right inferior frontal gyrus. Changes specific on euthymia include hyperactivations in the left superior temporal gyrus and hypoactivations in the basal ganglia, and changes specific to mania include hyperactivation in the basal ganglia. A meta analysis of fMRI studies reported underactivations in the inferior frontal gyrus and putamen and hyperactivation of the parahippocampus, hippocampus, and amygdala. State specific abnormalities were reported for mania and euthymia. During mania, hypoactivation was significant in the inferior frontal gyrus, while euthymia was associated with hypoactivation of the lingual gyrus and hyperactivation of the amygdala.

A meta analysis using region of interest (as opposed to statistical parametric mapping) analysis reported abnormalities across paradigms for euthymic, depressed, and manic subjects. In bipolar mania, reduced activity was reported in the superior, middle, and inferior frontal gyri, while increased activity was reported in the parahippocampal, superior temporal, middle temporal, and inferior temporal gyri. In bipolar depression, reduced activity was reported in the sgACC, ACC, and middle frontal gyrus. In euthymia, reduced activity was reported in the dlPFC, vlPFC, and ACC, while increased activity was reported in the amygdala. During studies examining response to emotional faces, both mania and euthymia were reported to be associated with elevated amygdala activity.

An activation likelihood estimate meta analysis of bipolar studies that used paradigms involving facial emotions reported a number of increases and decreases in activation compared to healthy controls. Elevated activity was reported in the parahippocampal gyrus, putamen, and pulvinar nuclei, while reduced activity was reported bilaterally in the inferior frontal gyrus. Compared to major depressive disorder, bipolar patients overactivated the vACC, pulvinar nucleus, and parahippocampus gyrus/amygdala to a greater degree, while underactivating the dACC. Bipolar subjects overactivated parahippocampus for both fearful and happy expressions, while the caudate and putamen were overactived for happiness and fear respectively. Bipolar subjects also underactivated the ACC for both fearful and happy expressions, while the IFG was underactivated for fearful expressions only. These results were interpreted as reflecting increased engagement with emotionally salient stimuli in bipolar disorder.

Specific symptoms have been linked to various neuroimaging abnormalities in bipolar disorder, as well as schizophrenia. Reality distortion, disorganisation, and psychomotor poverty have been linked to prefrontal, thalamic, and striatal regions in both schizophrenia and bipolar (Table below).

Symptom Dimension	Implicated Regions in Bipolar	Implicated Regions in Schizophrenia
Disorganisation	1. Hypofunction in the ventrolateral prefrontal cortex (vlPFC). 2. Hypofunction in the medial prefrontal cortex (mPFC)/ACC.	1. Hypofunction in the medial prefrontal cortex (mPFC). 2. Hypofunction in the dorsolateral prefrontal cortex (dlPFC). 3. Hypofunction in the cerebellum. 4. Hypofunction in the insula. 5. Hypofunction in the temporal cortex.
Reality Distortion	1. Functional abnormalities in prefrontal and thalamic regions.	1. Reduced grey matter in perisylvian and thalamic regions. 2. Hypofunction of the amygdala, mPFC and hippocampus/parahippocampus.
Psychomotor Poverty	1. Functional abnormalities in the vlPFC and ventral striatum.	1. Reduced grey matter in the vlPFC, mPFC and dlPFC. 2. Reduced grey matter in the striatum, thalamus, amygdala and temporal cortices.

Frontal Cortex

Different regions of the ACC have been studied in the literature, with the subgenual (sgACC) and rostral (rACC) parts being largely separated. Grey matter volume in the sgACC has been, albeit with some exceptions, found to be reduced in bipolar. Along with this, bipolar is associated with increased blood flow in the sgACC that normalises with treatment. Congruent with these abnormalities is a reduction in glial cells observed in post mortem studies, and reduced integrity of white matter possibly involving a hemispheric imbalance. Findings in the rACC are largely the same as the sgACC (reduced GM, increased metabolism), although more studies have been carried out on protein expression and neuronal morphology. The rACC demonstrates reduced expression NMDA, kainate and GABA related proteins. These findings may be compensating for increased glutaminergic afferents, evidenced by increased Glx in MRS studies. One VBM study reported reduced grey matter in the dACC. Inconsistent results have been found during functional neuroimaging of cognitive tasks, with both decreased and increased activation being observed. Decreased neuron volume and a congruent increase in neural density have been found in the dACC. Reduced expression of markers of neural connectivity have been reported (e.g. synaptophysin, GAP-43), which is congruent with the abnormal structural connectivity observed in the region.

The orbitofrontal cortex demonstrates reduced grey matter, functional activity, GAD67 mRNA, neuronal volume in layer I, and microstructural integrity in people with bipolar.

Although the role of acute mood states is unknown, grey matter volume is generally reported as reduced in the dlPFC, along with resting and task evoked functional signals. Signals of myelination and density of GABAegic neurons is also reduced in the dlPFC, particularly in layers II-V.

Neurochemistry

Magnetic Resonance Spectroscopy (MRS)

Increased combined glutamine and glutamate (Glx) have been observed globally, regardless of medication status. Increased Glx has been associated with reduced frontal mismatch negativity, interpreted as dysfunction in NMDA signalling. N-acetyl aspartate levels in the basal ganglia are reduced in bipolar disorder, and trends towards increased in the dorsolateral prefrontal cortex. NAA to creatine ratios are reduced in the hippocampus.

One review of magnetic resonance spectroscopy studies reported increased choline in the basal ganglia, and cingulate as well as a decreased in NAA in the dlPFC and hippocampus. State specific findings were reported to include elevated phosphomonoesters during acute mood states, and reduced inositol with treatment. Another review reported inositol abnormalities in the basal ganglia, and frontal, temporal and cingulate regions. The finding of a trend towards increased NAA concentrations in the dlPFC may be due to medication status, as treatment with lithium or valproate has been noted to lead to null findings, or even elevated levels of NAA in the frontal cortex. In unmedicated populations, reduced NAA consistently found in the prefrontal cortex, particularly the dlPFC.

One meta analysis reported no changes in MRS measured GABA in bipolar disorder.

Monoamines

Various hypotheses related to monoamines have been proposed. The biogenic amine hypothesis posits general dysregulation of monoamines underlies bipolar and affective disorders. The cholinergic aminergic balance hypothesis posits that an increased ratio of cholinergic activity relative to adrenergic signalling underlies depression, while increased adrenergic signalling relative to cholinergic signalling underlies mania. The permissive hypothesis suggests that serotonin is necessary but not sufficient for affective symptoms, and that reduced serotonergic tone is common to both depression and mania.

Studies of the binding potential of dopamine receptor D2 and dopamine transporter have been inconsistent but dopamine receptor D1’s binding potential has been observed to be decreased. Drugs that release dopamine produce effects similar to mania, leading some to hypothesize that mania involves increased catecholaminergic signalling. Dopamine has also been implicated through genetic “reverse translational” studies demonstrating an association between reduced DAT functionality and manic symptoms. The binding potential of muscarinic receptors are reduced in vivo during depression, as well as in post mortem studies, supporting the cholinergic aminergic balance hypothesis.

The role of monoamines in bipolar have been studied using neurotransmitter metabolites. Reduced concentration of homovanillic acid, the primary metabolite of dopamine, in the cerebrospinal fluid (CSF) of people with depression is consistently reported. This finding is related to psychomotor retardation and anhedonia. Furthermore, parkinson’s disease is associated with high rates of depression, and one case study has reported the abolishment of parkinson’s symptoms during manic episodes. The binding potential of VMAT2 is also elevated in bipolar I patients with a history of psychosis, although this finding is inconsistent with finding that valproate increases VMAT2 expression in rodents. One study on DAT binding in acutely depressed people with bipolar reported reductions in the caudate but not putamen.

Studies of serotonin’s primary metabolite 5-HIAA have been inconsistent, although limited evidence points towards reduced central serotonin signalling in a subgroup of aggressive or suicidal patients. Studies assessing the binding potential of the serotonin transporter or serotonin receptors have also been inconsistent, but generally point towards abnormal serotonin signalling. One study reported both increased SERT binding in the insula, mPFC, ACC and thalamus, and decreased SERT binding in the raphe nuclei in acutely depressed bipolar. Serotonin may play a role in mania by increasing the salience of stimuli related to reward.

One more line of evidence that suggests a role of monoamines in bipolar is the process of antidepressant related affective switches. Selective serotonin reuptake inhibitors and more frequently, tricyclic antidepressants (TCAs) are associated with between a 10%-70% risk of affective switch from depression to mania or hypomania, depending upon the criteria used. The more robust association between TCAs and affective switches, as opposed to more selective drugs, has been interpreted as indicating that more extensive perturbation in monoamine systems is associated with more frequent mood switching.

Hypothalamic Pituitary Adrenal Axis

Bipolar disorder is associated with elevated basal and dexamethasone elicited cortisol and adrenocorticotropic hormone (ACTH). These abnormalities are particularly prominent in mania, and are inversely associated with antipsychotic use. The incidence of psychiatric symptoms associated with corticosteroids is between 6% and 32%. Corticosteroids may precipitate mania, supporting the role of the HPA axis in affective episodes. Measures from urinary versus salivary cortisol have been contradictory, with one study of the former concluding that HPA hyperactivity was a trait marker, while a study of the latter concluded that no difference in HPA activity exists in remission. Measurement during the morning are thought to be more sensitive due to the cortisol awakening response. Studies are generally more consistent, and observe HPA hyperactivity.

Neurotrophic Factors

Brain derived neurotrophic factor levels are peripherally reduced in both manic and depressive phases.

Intracellular Signalling

The levels of Gαs but not other G proteins is increased in the frontal, temporal and occipital cortices. The binding of serotonin receptors to G proteins is also elevated globally. Leukocyte and platelet levels of Gαs and Gαi is also elevated in those with bipolar disorder. Downstream targets of G protein signalling is also altered in bipolar disorder. Increased levels of adenylyl cyclase, protein kinase A (PKA), and cyclic adenosine monophosphate induced PKA activity are also reported. Phosphoinositide signalling is also altered, with elevated levels of phospholipase C, protein kinase C, and Gαq being reported in bipolar. Elevated cAMP stimulated phosphorylation or Rap1 (a substrate of PKA), along with increased levels of Rap1 have been reported in peripherally collected cells of people with bipolar. Increased coupling of serotonin receptors to G proteins has been observed. While linkage studies performed on genes related to G protein signalling, as well as studies on post mortem mRNA concentration fail to report an association with bipolar disorder, the overall evidence suggests abnormal coupling of neurotransmission systems with G proteins.

Mania may be specifically associated with protein kinase C hyperactivity, although most evidence for this mechanism is indirect. The gene DGKH has been reported in genome wide association studies to be related to bipolar disorder, and it is known to be involved in PKC regulation. Manipulation of PKC in animals produces behavioural phenotypes similar to mania, and PKC inhibition is a plausible mechanism of action for mood stabilisers. Overactive PKC signalling may lead to long term structural changes in the frontal cortex as well, potentially leading to progression of manic symptoms.

Glycogen synthase kinase 3 has been implicated in bipolar disorder, as bipolar medications lithium and valproate have been shown to increase its phosphorylation, thereby inhibiting it. However, some postmortem studies have not shown any differences in GSK-3 levels or the levels of a downstream target β-catenin. In contrast, one review reported a number of studies observing reduced expression of β-catenin and GSK3 mRNA in the prefrontal and temporal cortex.

Excessive response of arachidonic acid signalling cascades in response to stimulation by dopamine receptor D2 or NMDA receptors may be involved in bipolar mania. The evidence for this is primarily pharmacological, based on the observation that drugs that are effective in treating bipolar reduced AA cascade magnitude, while drugs that exacerbate bipolar do the opposite.

Calcium homeostasis may be impaired across all mood states. Elevated basal intracellular, and provoked calcium concentrations in platelets and transformed lymphoblasts are found in people with bipolar. Serum concentrations of calcium are also elevated, and abnormal calcium concentrations in response to stimulation of olfactory neurons is also observed. These findings are congruent with the genetic association of bipolar with CACNAC1, an L-type calcium channel, as well as the efficacy of anti-epileptic agents. Normal platelets placed in plasma from people with bipolar disorder do not demonstrate elevated levels of intracellular calcium, indicating that dysfunction lies intracellularly. One possible mechanism is that elevated inositol triphosphate (IP3) caused by hyperactive neuronal calcium sensor 1 causes excessive calcium release. Serum levels of S100B (a calcium binding protein) are elevated in bipolar mania.

Mitochondrial Dysfunction

Some researchers have suggested bipolar disorder is a mitochondrial disease. Some cases of familial chronic progressive external ophthalmoplegia demonstrate increased rates of bipolar disorder before the onset of CPEO, and the higher rate of maternal inheritance patterns support this hypothesis. Downregulation of genes encoding for mitochondrial subunits, decreased concentration of phosphocreatine, decreased brain pH, and elevated lactate concentrations have also been reported. Mitochondrial dysfunction may be related to elevated levels of the lipid peroxidation marker thiobarbituric acid reactive substances, which are attenuated by lithium treatment.

Neuropathology

A number of abnormalities in GABAergic neurons have been reported in people with bipolar disorder. People with bipolar demonstrate reduced expression of GAD67 in CA3/CA2 subregion of the hippocampus. More extensive reductions of other indicators of GABA function have been reported in the CA4 and CA1. Abnormal expression of kainate receptors on GABAergic cells have been reported, with reductions in GRIK1 and GRIK2 mRNA in the CA2/CA3 being found in people with bipolar. Decreased levels of HCN channels have also been reported, which, along with abnormal glutamate signalling, could contribute to reduced GABAergic tone in the hippocampus.

The observation of increased Glx in the prefrontal cortex is congruent with the observation of reduced glial cell counts and prefrontal cortex volume, as glia play an important role in glutamate homeostasis. Although the number and quality of studies examining NMDA receptor subunits is poor, evidence for reduced NMDA signalling and reduced contribution from the NR2A subunit is consistent.

Decreased neuron density and soma size in the ACC and dlPFC has been observed. The dlPFC also demonstrates reduced glial density, a finding that is less consistent in the ACC. The reduction in cell volume may be due to early stage apoptosis, a mechanism that is supported by studies observing reduced anti-apoptotic gene expression in both peripheral cells and neurons, as well as the reduction in BDNF that is consistently found in bipolar. Reductions in cortical glia are not found across the whole cortex (e.g. somatosensory areas demonstrate normal glial density and counts), indicating that systematic dysfunction in glial cells is not likely; rather, abnormal functionality of connectivity in specific regions may result in abnormal glia, which may in turn exacerbate dysfunction.

Dendritic atrophy and loss of oligodendrocytes is found in the medial prefrontal cortex, and is possibly specific to GABAergic neurons.

Immune Dysfunction

Elevated levels of IL-6, C-reactive protein (CRP) and TNFα have been reported in bipolar. Levels of some (IL-6 and CRP) but not all (TNFα) may be reduced by treatment. Increases in IL-6 have been reported in mood episodes, regardless of polarity. Inflammation has been consistently reported in bipolar disorder, and the progressive nature lies in dysregulation of NF-κB.

Causes of Mental Illness

Published on 12/20/2019 by Andrew MarshallLeave a comment

Currently, mental illness is thought to be caused by a complex interaction of factors, including the following:

Hereditary;
Biologic (physical factors);
Psychologic; and/or
Environmental (including social and cultural factors).

Research has shown that for many mental health disorders, heredity plays a part. Often, a mental health disorder occurs in people whose genetic make-up makes them vulnerable to such disorders. This vulnerability, combined with life stresses, such as difficulties with family or at work, can lead to the development of a mental disorder.

Also, many experts think that impaired regulation of chemical messengers in the brain (neurotransmitters) may contribute to mental health disorders.

Brain imaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), often show changes in the brains of people with a mental health disorder.

Thus, many mental health disorders appear to have a biologic component, much like disorders that are considered neurologic (such as Alzheimer disease).

However, whether the changes seen on imaging tests are the cause or result of the mental health disorder is unclear.