Unipolar or Bipolar Disorder – What’s all the Fuss About?

HOW DO WE CONCEPTUALISE THE DIFFERENCE?

Let’s take a page from Scott Peck (Psychiatrist and author of The Road less Travelled);

Abandon the urge to simplify everything, to look for formulas and easy answers, and to begin to think multidimensionally, to glory in the mystery and paradoxes of life, not to be dismayed by the multitude of causes and consequences that are inherent in each experience — to appreciate the fact that life is complex.

Let’s take a look at what depression and mania look like in the brain.

Please note that the diagrams below are simplistic models linking certain brain areas to symptoms with 3 key neurotransmitters involved (There are likely other neurotransmitters involved which we haven’t covered). What is uncertain is the exact role of these neurotransmitters in the genesis of symptoms and the syndrome as whole. Nonetheless this understanding can be translated to clinical practice and applied in treatment. For example; we know that elevated dopamine in the mesolimbic system (ventral tegmental area to the nucleus accumbens) is associated with psychotic symptoms. Dopamine antagonists can treat psychotic symptoms.

We also know that frontal (PFC) cortico-striatal areas mediate hedonic drive and cognitive functions which relies on an optimal balance of Noradrenaline / Norepinephrine (NA / NE) and Dopamine (DA). Dopaminergic agonists e.g Psychostimulants can treat cognitive symptoms. See more in ADHD or Melancholic Depression. 

Depression in the Brain [Stahl, 2013]

Mania in the Brain

Considering the pathways and, at a minimum, taking into account three neurotransmitters (NE, Serotonin and Dopamine), simple mathematics tells us that if there are 10 pathways involved and you had to pick three pathways (r) from a choice of 10 pathways (n) the number of permutations is equal to 120.

If one were to add additional neurotransmitters (e.g Glutamate, ACh), the possible permutations and combinations increase significantly.

In patient terms, imagine you have one patient with ‘decreased’ dopamine in the frontal lobe and ‘increased’ dopamine in the limbic system whilst another patient may have ‘reduced’ serotonin and dopamine in the limbic system and ‘increased’ dopamine in frontal lobe; add on other neurotransmitters and a different combination arises and the list goes on and on.

Important: Please note that the above explanation is simplistic and is not to be taken as reduced serotonin or dopamine causes depression.

There is no clear and convincing evidence that monoamine deficiency accounts for depression, i.e., there is no “real” monoamine deficit” [Stahl, 2013].

Linking the heterogeneous clinical manifestations of Major Depressive Disorder (MDD) to deficiency of a molecule is too simplistic and may misguide our understanding of the complexity of this disorder. [Liu et al, 2017]

The purpose of this article is to provide a simplified model that can be applied to clinical practice based on the medications available and their respective psychopharmacology.

For a more in-depth understanding please read Neurobiology of Depression – A Simplified Guide

WHAT'S THE SOLUTION?

Even to the untrained eye, the above images scream out loud that it is extremely difficult to lump the disorders into Unipolar and Bipolar Disorder. The variables that influence these pathways, the uncertainty in neurobiology, notwithstanding the permutations and combinations of the pathways involved, show us that an alternative approach (as opposed to thinking in labels) is required in treatment.

Take one example below

A patient presenting with depressed mood at one point (in this case let’s say due to decreased frontal dopamine and noradrenaline) may very easily have mixed features (racing thoughts, psychomotor agitation, irritability etc.) due to increased dopamine in the limbic system which from a treatment perspective will require treatment of his/her mood state by increasing dopamine in frontal lobe and reduction of racing thoughts, agitation and irritability by reducing dopamine in the limbic system through either dopaminergic blockade (antipsychotic-mood stabilisers like D2-5HT2 blockers) or mood stabiliser GABA potentiators that indirectly have an inhibitory effect on limbic dopamine.

Similarly, depression may occur due to dysregulation of serotonin in the cortico-limbic system. Dysconnectivity within prefrontal–limbic system might be more related to the dysregulation of negative affect, whereas dysconnectivity within prefrontal–striatum system might influence more on positive affect processing. [He et al, 2019].

A study provided us a glimpse into how antidepressants may potentially act on these pathways. Researchers used fMRI to measure the neural response on antidepressants to rewarding (sight and/or flavor of chocolate) and aversive stimuli (sight of moldy strawberries and/or an unpleasant strawberry taste). [McCabe et al, 2010]

Citalopram (SSRI) reduced activation to the chocolate stimuli in the ventral striatum and the ventral medial/orbitofrontal cortex.

In contrast, reboxetine (NARI) did not suppress ventral striatal activity and in fact increased neural responses within medial orbitofrontal cortex to reward. Citalopram also decreased neural responses to the aversive stimuli conditions in key “punishment” areas such as the lateral orbitofrontal cortex. Reboxetine produced a similar, although weaker effect.

Thus, while the study tells us that serotonergic and noradrenergic antidepressants act differentially on these pathways, it does not tell us exactly how.

It is therefore not surprising that terms like bipolar depression, mixed affective states, atypical depression, major depression with mixed features, cyclothymia, rapid cycling have proliferated to explain these permutations and combinations. What this tells us (especially if they present with no clear cut symptoms of mania or depression) is that the human brain is far too complex to box people into categories.

A diagnostic label is helpful, but one must understand its limitations. Osler’s quote comes to mind.

Ask not what disease the person has, but rather what person the disease has.

It is helpful to provide a formulation along with the provisional ‘diagnostic label’ as part of psychoeducation. Treatment can then proceed by neuromodulation and identifying modifiable biological and psychological factors. Psychiatric Formulation Demystified – The Sherlock Holmes Way

In view of the diagnostic complexity, it is thus not surprising that the DSM-5 felt the need to include the disorder – Major Depressive Disorder with Mixed Features.

Mixed features associated with major depressive episode have been found to be a significant risk factor for the development of bipolar I or bipolar II disorder. As a result, it is clinically useful to note the presence of this specifier for treatment planning and monitoring response to treatment. 

CLINICAL PEARLS

The WHIPLASHED mnemonic is an excellent tool to aid diagnosis of Bipolar Depression. [Pies, 2007]

Understanding which patients may have a ‘bipolar trait’ may –

• Influence the choice of treatment
• Identify individuals that may be a greater risk of developing of bipolar disorder
• Appropriately inform women about the risk of mood disorders in the peri-natal period
• Inform appropriate caution with the use of antidepressants in such patients due to the risk of inducing a switch.

DON'T GET LOST - GET TO KNOW YOUR LANEWAYS

It is important to remember that the causes of neurotransmitter dysregulation may be due to a multitude of reasons (e.g. thyroxine deficiency, Vit B12 deficiency, frontal injury, vascular factors, etc.).

For example, if the person is ‘deficient’ in serotonin or dopamine due to a deficiency in essential elements required in the production of serotonin, dopamine (e.g. Zinc, Mg, B6, Iron ) or if hormones that are required for enhancing the sensitivity of serotonin on 5HT receptors are deficient (e.g. Thyroid hormone) then prescribing antidepressants may not provide optimal benefit.

For example; Iron deficiency can cause dysregulation of monoaminergic system. Inhibition of iron uptake into dopaminergic neurons not only causes mitochondrial damage, but also reduces dopamine levels and evoked abnormal activity of dopamine receptors. [Matak et al, 2016]

Translationally in clinical practice we see this as part of restless leg syndrome which is known to be associated with Iron deficiency anemia and treatment includes dopamine agonists (e.g pramipexole).

It’s like getting to know the neighbourhood laneways.  If you don’t know them well, you won’t be able to help someone who can’t find their way.

WHAT WOULD EINSTEIN DO?

We can take a page about problem-solving from Einstein –

If I had an hour to solve a problem (e.g unipolar or bipolar), I’d spend 55 minutes thinking about the problem (causes and pathways involved) and 5 minutes thinking about solutions (treatment). (brackets are my insertions)

The take home message here is to spend time deciphering the problem. The solution is the end product once the problem is well understood. The issue of causality is particularly important because depression and bipolar disorder can present due to a range of causes and although the same pathways are affected, the causes may be different.

Think of the pathways as a system of interconnected roads. These roads may be blocked by roadblocks, falling boulders, flooding, road damage etc. A single broad brush approach will not solve the different problems; in some cases, it may even be dangerous.

The same applies to disorders of the brain. The key is to understand what is affecting these pathways; if it is a neurotransmitter abnormality based on our current level of understanding (e.g manic symptoms linked to elevated mesolimbic dopamine) then psychiatric medications may help. If, however, there are alternate issues, other treatments may be required as we saw here and here. Addressing psychological factors are also important.

Solving such a conundrum in clinical practice requires going back to a basic problem-solving approach. Listen, gather information, build a hypothesis based on possible causality and test the hypothesis. This is what makes a psychiatric formulation powerful in problem-solving.

The article is not intended to deter from diagnosis, but to understand the limitations of a label. A human being is much too complex to explain in a single diagnosis. So the next time you come across this question, it may be OK to step outside the poles.

Want to learn more? Check out how biological deconstruction is used in medical treatment of depression and OCD.

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