Tag Archives: Major depressive disorder

The Four Neural Sub-Types of Depression

Regular readers of The Mouse Trap will be familiar with my obsession with knowing how nature is carved at its joints or in other words what are the natural categories or basic kinds.

Anhedonia (The Graduate album)

Anhedonia (The Graduate album) (Photo credit: Wikipedia)

This translates into thinking a lot about what are the fundamental drives, basic emotions and personalty traits and what taxonomic system of mental illness is most reflective of underlying fundamental nosological differences.

While synthesizing the work of others, has great value, and one derives many valuable theoretical insights based on such musings; there is nothing better than finding empirical studies that shed some light on such matters.

For example, I have argued that one set of disorders that arise form emotional polarity of fear/interest is Anxiety disorders and Obsession disorders. When fear is disproportional/ inappropriate  to circumstances, it leads to anxiety; when interest is disproportional/ inappropriate it leads to Obsession. Fear and interest though opposed are two separate constructs as per the first tenet of positive psychology that good is not the absence of bad.

Similarly, the set of disorders that arise form sadness/ Joy polarity is depressive disorders and manic disorders. I am deliberately using plural form while defining depressive/ manic disorders as they contain sub-types – as we  will soon see in the case of depression.

Now while depression is characterized by excessive low affect (sadness), one way to conceive Mania is as having excessive energy; the opposite of manic symptoms thus might be conceived of as fatigue or anergia. Anxiety is of course marked by excess anxiety while Obsession is too much interest; a possible opposite of obsession may be anhedonia– a sort of disinterest or apathy.

Now, its common to find depression and anxiety disorders comorbid with each other and just like treating bipolar as well as schizophrenia under one umbrella of psychosis, one may conceivably treat depression/ anxiety / anergia and anhedonia under a common nomenclature- in this case that of depression.

But we are perhaps getting ahead of ourselves. Lets backtrack a bit and go straight to this new study that found four neural subtypes of depression.

Basically, Liston and colleagues, used resting state fMRI to look at the functional connectivity of depressed patients and developed an algorithm to predict who has depression and who does not have in a sample consisting of both depressed patients and healthy controls. They found abnormal functional connectivity in frontostraital and limbic systems in teh depressive patients.

They also used clustering techniques to find that their depressive subset of patients clustered around two dimensions- one of which they called anxiety dimension and the other anhedonia. When one takes into account that there could be 2×2 = 4 combinations of anxiety and anhedoinia they found that their patients neatly clustered in those four quadrants.

If you note in the figure 1f accompanying the article,

  • cluster 1 subjects have low scores on anhedonia and high scores on anxiety
  • cluster 2 subjects have neither anxiety nor anhedonia
  • cluster 3 have high anhedonia but low anxiety
  • cluster 4 have both high anxiety and high anhedonia

The authors note that all subjects had low mood (sadness, hoplessness, helplessness) and that is why they were classified as depressed patients in the first place. The core depressive signature was also associetd with anergia and anhedonia with majority of patients showing these symptoms across all subtypes.

They also found slightly different neural signatures for all the four subtypes. For eg. cluster 1 & 4 characterized by high anxiety had reduced frontoamygdalar connectivity, linking it with fear circuit. Cluster 3 & 4 were associated with hyper connectivity between thalamic and frontostriatal networks and had high anhedonia and psychomotor retardation associated with them. And cluster 1 & 2 had reduced connectivity between anterior cingulate and orbitofrontal coretx involved in reward and incentive salience and guess what they showed anergia or fatigue.

To me it seems apparent that what we are seeing here are different effects of low mood, anxiety, anhedonia and anergia playing out as four clusters.

Cluster 3 I would classify as primarily anehdoina related; cluster 4 as primarily anxiety related; cluster 1 may be thought of as  anergia related and clusetr 2 as pure depression or low mood related.

If my hunches are true we should find similar subdivisions in diagnosed anxiety disorders, obsessive disorders , manic disorders too. Of  course that is an empirical fact to be proved.

Depression and its Antecedents

Today I will approach the problem of depression, but from a particular vantage point – that steeped in cognitive theory and informed by the work of Martin Seligman.

English: Abraham Lincoln, the sixteenth Presid...

English: Abraham Lincoln, the sixteenth President of the United States. Latviešu: Abrahams Linkolns, sešpadsmitais ASV prezidents. ?????? / Srpski: ??????? ???????, ????????? ?????????? ?????????? ????????? ??????. (Photo credit: Wikipedia)

There have been other views about depression- a psychoanalytical one whereby depression was deemed as rage turning upon inwards and directed towards the self; and a biomedical one whereby depression is considered a disease of the brain/body- imbalances in neurotransmitters etc. . Seligman rejects both models and considers depression (even clinically defined) as just the other extreme of response to loss etc. This is important to note as unipolar depression, clinically defined, is usually considered a  type rather than a degree phenomena, i.e. people in depressive phase are qualitatively different from those who are not clinically depressed as per the prevalent model.However, note that even Seligman considers the mild form of depression as distinct from sadness.

The theory of depression that Seligman and colleagues came up with is based on his famous experiments with dogs whereby experimental dogs were subjected to uncontrollable mild shocks while the control dogs either received no shocks or shocks that they could stop and control. When the dogs who were subjected to uncontrollable shocks were placed in anew chamber whereby they could escape shocks by climbing over a  low barrier, they sat passively. They had learned or internalized that nothing they do with respect to shocks makes the shocks go away and had even generalized it to new situations when things were actually under their control. Also the feelings of helplessness reflected in many diverse behaviors like less aggressiveness or exploration etc and was sort of generalized across situations too.  So not only the experimental dogs made permanent attributions about their lack of control, but also pervasive attributions and thus became depressed.

Seligman and colleagues designed and executed similar experiments with rats and also humans. Using these experiments they were able to create a model of depression. That model of depression requires different things to come together, but typically as its called learned helplessness model of depression, the focus has been on the learned helplessness following a loss of control.

The different components of the model, when explicated, have different implications for treatment/ prevention. To start with before the process can start one has to have loss of control – if our environments provided more opportunity for control over our experiences and in general if people learned to feel more in control of their life, despite losses and all, then the chain stops at its beginning itself. While some losses are inevitable, say loss of loved one, other losses like pink slips can be minimized and then no matter what the loss is , one can choose one’s own attitude towards the loss – the last of human freedom’s as per Frankl.

Once loss/ dejection/rejection/ loss of control has happened, almost all of us will temporarily become helpless. However, becoming helpless is not same as becoming mildly depressed too. For some of us who have a habitual pessimistic explanatory style, in terms of seeing the negative events in our lives as being permanent and pervasive, the learned helplessness turns into momentary , mild depression. We have sad affect, disturbed sleeping, eating etc. However, for those who have optimistic explanatory styles, we re-bounce from the learned helpless and do not become depressed. So changing the habitual explanatory style is another intervention opportunity.

Finally, the mild and momentary depression become full-fledged clinical unipolar depression, when the symptoms continue for 2 weeks or more and as per Seligman this happens when one adds a ruminating thinking style to the mix. Thus a person who has a pessimistic style and also keeps thinking about his own thoughts is more likely to get clinically depressed. Again , if we can prevent or reduce rumination we can prevent the clinical variant.

Cognitive behavioral therapy , which has been found to be quite effective for depression, has been shown to work on some of these aspects  increasing optimistic explanatory style and challenging negative automatic thoughts  but probably can be augmented by focusing on preventing rumination and story-editing techniques to re-frame issues of loss and control.

In the end, in my view depression has complex roots – some steeped in biology and temperament, while others due to environmental stressors and our reactions to them. A clearer understanding of the learned helplessness model of depression is likely to aid in therapy.

Why is the world vivid in mania, but bleak in depression?

Down in a hole
Image by ParanoidMonk via Flickr

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No, I am not speaking metaphorically. Quite literally,there has been accumulating evidence that sense are sharpened and have great acuity in mania while they are dulled in depression and the effects can be seen within the same individual over time as he/she suffers from manic/depressive episodes.

The latest study to add to this literature is by Bubl et al that found that depressive people’s brain registered lesser contrast than that registered by normal control brains when presented with same black and white images. They used pattern electroretinogram (PERG) to find whether the contrast gains registered by depressive retinas (those suffering from MDD) were different from those of controls and they found a strong and significant association with the severity of the depression.

I have covered earlier studies that found that sense of taste was compromised in depression (and enhanced in mania) and similarly that the sense of smell showed similar effects. Some snippets from the earlier posts:

What this means is that if you increase the amount of serotonin in the brain, then the capacity to detect sweet and bitter tastes is increased; if you increase noradrenaline levels those of detecting salty and bitter tastes is augmented; while a general increase in anxiety leads to better bitter taste detection. This also means that an anxiety state produces more bitter taste perception whereas a depressive state (characterized by low serotonin) is marked by bland sense of taste with marked inability to detect sweet and bitter tastes. A stressed state , marked by abundance of noradrenaline, would however lead to more salty and bitter taste perception.

and…

In one of my earlier post on depression, I had commented on the fact that those suffering from depression have less sensitivity to sweet and bitter tastes and as such may compensate by eating more sugar thus leading to the well documented diabetes – depression linkage.

In a new study it has just been discovered that not only depressives have bland sense of taste, their sense of smell is also diminished and they may make compensations by using greater amounts of perfume. Overall it seems that those suffering from depression will have bland subjective experience of flavor(which is a combination of both smell and taste) and thus may even not really find what they eat to be tasty.

Further on, I speculate prophetically that blander vision will also be found:

To me, this is an important finding. To my knowledge no research has been done in other sense modalities (like vision), but there is every reason to think that we may discover a bland sense of vision in depression. Why do I surmise so? this is because there is extensive literature available regarding the manic state and how things seem ‘vivid’ during that state including visual vividness. If depression is the converse of Mania, it follows that a corresponding blandness of vision should also be observed in those who are clinically depressed.

We also know that in extreme or psychotic forms of Mania, auditory hallucinations may arise. I am not suggesting that hallucinations are equal to vividness, but I would definitely love to see studies determining whether the auditory sense is heightened in Mania (maybe more absolute pitch perception in Mania) and a corresponding loss of auditory absolute pitch perception in depression. If so found, it may happen that music literally becomes subdued for people with depression and they sort of do not hear the music present in everyday life!

Whether other sense like touch, vestibular/ kinesthetic , proprioception (a heightened sense of which may give rise to eerie out-pf-body experiences in Mania) are also diminished in depression is another area where research may be fruitful.

Of course I have also speculated about the others senses and would love to hear studies supporting/contradicting this thesis. But given that senses are attenuated in depression and exaggerated in mania the question remains why? Which brings me to the topic of this post- why is the world bleak /bland to a depressive and vivid for a manic?

This was also the question asked by Mark Changizi (@Mark_Changizi) on twitter with respect to this new study uncovered today and I replied that this may be due to broaden-and-build theory being applied to sensory domain or sensory gating phenomenon differentially acting in manic/ depressive states, while Mark was of the opinion that it might be the result of physiological arousal with arousal being the variable of interest controlling whether the sense remain acute or dull?

I do not see the two views necessarily contradictory and it may be that chronic affect per se activates arousal and that is the mediating variable involved in its effect on senses; and we can design experiments to resolve this by measuring the effect of state sadness/ happiness/arousal on visual acuity (if the effects of state manipulations are big enough); howsoever, I woudl like to elaborate on my broaden and build theory.

In the cognitive, psychological and psychosocial domains the broaden and build theory of positive affect is more or less clearly elaborated and delineated. I wish to extend this to the sensory domain. I propose that chronic positive affect signals to our bodies/brains that we can afford to make our attention more diffuse, let senses be perceived more vividly as we have more resources available to process incoming data; conversely in a chronic low affect state we might like to conserve resources by narrowing focus/ literally narrowing the range of sensory inputs/reducing the sensitivity of sense organs and pool those resources elsewhere.

I know this is just a hypothesis , but I am pretty convinced and would love to hear the results of experiments anyone conducts around this theory.
Bubl, E., Kern, E., Ebert, D., Bach, M., & Tebartz van Elst, L. (2010). Seeing Gray When Feeling Blue? Depression Can Be Measured in the Eye of the Diseased Biological Psychiatry, 68 (2), 205-208 DOI: 10.1016/j.biopsych.2010.02.009

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Autism, Psychosis and circadian clock

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Diagram illustrating the influence of dark-lig...
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I recently came across this post by Michelle Dawson that states the thesis that one of the abnormalities in Autism spectrum disorders is due to abnormal circadian clock functioning. More specifically, the clock is internally driven and has a greeter ‘free running’ period and does not entrain readily to environmental and social clues.

Autistics whose sleep-wake cycles carry on independently from environmental and social cues are said to be “freerunning.”
The usual response to freerunning in autism is to see this as an autism-related sleep disorder. There is very preliminary evidence that freerunning autistics can be successfully treated with melatonin. Bourgeron (2007) refers to a short case study about an autistic whose free-running was remediated by melatonin treatment.

If you feel a bit overwhelmed by all the circadian clock related terminologies, I wholeheartedly recommend BoraZ’s clock tutorial series , especially this one.

Dawson further says:

Glickman (2010) speculates that some autistics’ failure to chain our sleep-wake cycles to environmental cues may arise from our atypical perception. My totally wild guess might be that an extreme freerunning phenotype in autism may be contributed to in part by cognitive versatility in autism, which would result in perceived environmental cues affecting sleep-wake cycles in an optional rather than mandatory way.

I wont speculate about the reasons behind why autistics have a greater free-running period and less entrainment to social and environmental clue, but I woudl say that instead of giving them flexibility, I would presume that this locks them into their internal rhythms, while others are more responsive to environment and better adapted. That brings me to the opposite phenotype of ASD…the psychotic phenotype shown by Schizophrenics, depressives and Bipolars.

As per this PLOS Genetics article:

The contribution of the circadian regulatory system, arising from conflicts between internal biological clocks and environmental (solar) and social clocks, is evident in affective disorders. All major affective disorders (such as unipolar depression, OMIM #608516; bipolar disorder, and schizophrenia, OMIM #181500) include circadian phase disturbances in sleep, activity, temperature, and hormone levels (for reviews see [84]–[86]). Moreover, there is evidence that if rhythms can be altered/stabilised using relevant therapies, improvements in the primary symptoms can occur. For example, in some instances sleep deprivation has an antidepressant effect in patients [87]. Conversely, many disorders with a primary anomaly in the circadian system are associated with depressed mood. Seasonal affective disorder (SAD; OMIM #608516) is a common condition where depressive symptoms occur during shorter winter days [88]–[90]. Two inherited sleep phase disorders, familial advanced sleep phase syndrome (FASPS; OMIM #604348) and delayed sleep phase syndrome (DSPS), are both associated with abnormal affective states [91],[92]. Furthermore, individuals with a behavioural preference for “eveningness” have a greater tendency to develop depression [93].

The above to me seems hypersensitivity to social and environmental cues in affective/psychotic disorders. contrast this with ASD description by the same authors:

Other behavioural disorders with circadian and sleep-related disturbances include autism spectrum disorders (ASD) (OMIM %209850) [81]). Behavioural disturbances in ASD may arise in part from an inability of an individual’s circadian oscillator to entrain to environmental and social cues. One specific correlate of ASD is a low level of melatonin, and one of the enzymes critical in the synthesis of melatonin, acetylserotonin-O-methyltransferase (ASMT, OMIM *300015), is implicated as a susceptibility gene for ASD [82].

The role of melatonin seems to provide a clue. In autism, there seems to be low levels of melatonin and perhaps hypo-sensitivity to melatonin changes. In contrast Bipolar is marked by hypersensitivity of Melatonin receptors:

It has been suggested that a hypersensitivity of the melatonin receptors in the eye could be a reliable indicator of bipolar disorder, in studies called a trait marker, as it is not dependent on state (mood, time, etc.). In small studies, patients diagnosed as bipolar reliably showed a melatonin-receptor hypersensitivity to light during sleep, causing a rapid drop in sleeptime melatonin levels compared to controls.[58] Another study showed that drug-free, recovered, bipolar patients exhibited no hypersensitivity to light.[59] It has also been shown in humans that valproic acid, a mood stabilizer, increases transcription of melatonin receptors[60] and decreases eye melatonin-receptor sensitivity in healthy volunteers[61] while low-dose lithium, another mood stabilizer, in healthy volunteers, decreases sensitivity to light when sleeping, but doesn’t alter melatonin synthesis.[62] The extent to which melatonin alterations may be a cause or effect of bipolar disorder are not fully known.

The above is not the only source implicating Bipolar disorder and circadian clock dysfunction., See more here and here. The big question is not whether ASD and Affective disorders are both circadian rhythm disorders, but the big question is whether they show opposite phenotypes with respect to circadian clocks- one showing too little entrainment while the other too much?
Barnard, A., & Nolan, P. (2008). When Clocks Go Bad: Neurobehavioural Consequences of Disrupted Circadian Timing PLoS Genetics, 4 (5) DOI: 10.1371/journal.pgen.1000040

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stress and neurogenesis: the orchid -dandelion effect

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Orchid
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Chronic stress in mice leads to the ‘learned helplessness‘ model of depression in mice. Also, from studies in humans as well as other animals we know that chronic stress is a risk factor and cause for depression and this is mediated by the interactive effects of two stress related systems: “the neural substrate for the organism’s stress response comprises two anatomically distinct but functionally integrated circuits, the corticotropin-releasing hormone CRH system and the locus coeruleus–norepinephrine LC-NE system.”

The relation between cortisol level/ activity in the CRH/LE-NE system and stress related maladaptation is not simple , but the relationship is complex.

There are many theories of depression. A finding that has gained ground in recent years is the enhanced neurogenesis due to administration of anti-depressants and how the action of anti-depressants may be due to their enhancing neurogenesis effects.

However this new study in PNAS, conducted on mice,  casts doubt that the relation between stress/depression and neurogenesis is simple. It seems the relation is as complex as that between stress/depression and the cortisol levels.

I would first like to briefly summarize the findings of the study:

  • chronic stress paradigm used was that of social defeat (cohabitation with a socially dominant conspecific). 10 days of this social defeat were administered. this typically leads to social avoidance behaviors and these behaviors are correlated with other depressive phenotypes.
  • after 10 days when social avoidance (time interacting with a potential friendly con-specific) was measured it was found that about half the mice exhibited social avoidance and were sensitive to the stress; the rest of the half were ‘resilient’ and did not differ from control mice (not exposed to chronic social defeat) in their social avoidance.
  • all mice, both resilient and sensitive , showed decreased proliferation in subgranular zone (SGZ) for new cells immediately after stress exposure. This effect disappeared / normalised after 24 hrs.
  • Cell survival for cells created before stress exposure was not affected by stress exposure.
  • cell survival for neurons created 1 day after stress exposure was enhanced selectively for those mice that were susceptible or sensitive to stress, but was not enhanced for the resilient mice or the mice taken as a whole.
  • when the mice were irradiated, before stress exposure,  to prevent neurogenesis, then the social avoidance behavior, even in susceptible mice disappeared. It is thus evident that social avoidance is mediated by increased neurogenesis post-stress exposure in the susceptibel mice.

Overall, the results I believe are clearly in favor of conceptualizing the susceptible mice as ‘orchid’ mice – having enhanced tendency for neurogenisis following positive/negative events of interests. they are biologically sensitive to context and exhibit neurogenesis reactivity similar to stress reactivity shown by orchid children. Given a positive life experience the increased neurogenesis post-event helps in having happy memories and cognition s and better functioning; preponderance of negative life vents in contrast lead to more negative and longlasting cognitions and memories leading to reduced functioning. Of course the dandelion mice are resilient and not that much affected by chronic stress. However, they would also not be able to make best use of environment in good conditions.

The only hiccup I see in the whole scheme of things is the effect of anti-depressants on neurogenesis and my earlier theorizing that cells may die under repetitive stress and reduced or absent neurogenisis would be a prime factor in depression. However, the relation between neurogenesis and stress will be , I am sure, complex and needs to be settled empirically, rather than theoretically.  However one thing is clear, neurogenesis has a rpime role to play in depression , mediated perhaps by, chronic stress exposure and genetic diatheisis (orchid-dandelion effect).

I am excited and would love to hear of more papers that are addressing this new trend in depression – neurogenesis research keeping in mind the biological sensitivity to context thing too.

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Lagace, D., Donovan, M., DeCarolis, N., Farnbauch, L., Malhotra, S., Berton, O., Nestler, E., Krishnan, V., & Eisch, A. (2010). Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance Proceedings of the National Academy of Sciences, 107 (9), 4436-4441 DOI: 10.1073/pnas.0910072107

Chronic stress, neurogenesis and depression

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Diagram of hippocampal regions in a rat brain....
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Chronically stressful life events have been shown to lead to depression. Chronic stress leads to hyperactivity of HPA axis leading to more glucocorticoids (cortisol) in the human body. This excess cortisol in term is proposed to underlie the affective symptoms of depression. Also, depressive people have been found to have up to 20% smaller hippocampal volume, and a recent theory is gaining ground that depression is due to reduced neurogenesis. Even if the entire spectrum of depressive symptoms is not due to reduced neurogenesis and atrophied or smaller hippocampus, at least the cognitive symptoms of depression are largely due to this.

I stumbled upon a commentary by Robert Sapolsky that although is 10 years old, but I still found interesting and worth bringing to notice of my dear readers. In it Sapolsky looks at a study by Czeh et al that found evidence linking reduced proliferation in dentate gyrus and a shrunken hippocampus to depressive stress as modeled by psycho-social stress paradigm in tree shrew. Also, they found that an antidepressant, tianeptine, reversed the effects of stress by restoring proliferation and hippocampus size and thus reversing symptoms of depression. However the level of glucorticiods were still higher, after anti-depressant treatment, and thus it is apparent that anti-depressants work downstream of stress induced increase in glucorticoids.

Sapolsky believes that the data support either of models presented in figure 1A or figure 1B i.e. the increased glucocrticoids can lead to shrinkage of hippocampus directly or through their effect on affective symptoms. I believe figure 1C is also possible and its not necessarily incompatible with 1A or 1B and that increased stress may lead to increased cortisol- may lead to reduced neurogenesis may lead to shrinkage of hippocampus and which may in turn lead to affective and cognitive symptoms.

An alternative to reduced neurogenesis/ proliferation theory is the dendritic atrophy/ neurotoxicity theory that posits that shrinkage of hippocampus is due to cell death/ white matter loss. This again is a possibility but the evidence in favor of reduced neurogenesis is growing and becoming strong by the day.

Overall the new paradigms in depression research that look beyond serotonin or mono amine imbalance is a welcome trend and hopefully would lead to better interventions and prevention strategies and not just better pharmaceutical innovations. Its time one realized the rile chronic stress play sin depression and how that can be easily prevented to reduce the mental health burden.

Sapolsky, R. (2001). Depression, antidepressants, and the shrinking hippocampus Proceedings of the National Academy of Sciences, 98 (22), 12320-12322 DOI: 10.1073/pnas.231475998
Czeh, B. (2001). Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine Proceedings of the National Academy of Sciences, 98 (22), 12796-12801 DOI: 10.1073/pnas.211427898

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