How to Treat Depression by Using Biological Deconstruction – Case Files of a Patient with OCD and Depression

WHAT PARTS OF THE BRAIN ARE INVOLVED IN OBSESSIVE COMPULSIVE DISORDER?

Learning Point 1 –

The main circuits involved in OCD are the Cortico-thalamic-striatal- cortical loop (CTSC). Overactivation of this ‘worry loop’ is responsible for the development of obsessions. Selective Serotonin Reuptake Inhibitors (SSRI’s) at higher doses are effective in addressing the malfunctioning in this critical loop to treat the OCD. [Stahl’s essential psychopharmacology, 2013]

Read more on neurobiology, assessment and management of OCD

CURRENT PRESENTATION

It was difficult to obtain a coherent history due to significant slowing of thought and speech.

Jane Doe presented with depressed mood, anhedonia, anergia, significant fatigue and cognitive difficulties including short-term memory deficits, poor attention, and concentration with executive functioning deficits.

She also had ruminations, i.e. worries and intrusive thoughts related to the obsessive-compulsive disorder.

The psychologist notes stated –

Jane Doe presents with severe lethargy, she is falling asleep during the day; on one occasion when she was working at a client’s house and this was noticed and commented upon by the client. She also describes minimal if any interest or pleasure in many things, little or no joy.

Learning Point 2 –

The above symptoms indicate the presence of depression. However, when we deconstruct the diagnosis we find that the symptoms involve different brain areas and different neurotransmitters.

 

The above diagrams indicate that all three neurotransmitters are involved, and BOTH Frontal Lobe and Limbic system are involved. Sertraline would assist with the serotonin-related aspects, but the DA and NE are unaddressed in this patient. Activation of Serotonin can also reduce DA and NA in the PFC via 5HT2A and 5HT2C activation of GABA neurones which in turn reduce dopamine.

One of the major predictors of a poor response to antidepressant treatment (particularly those that target serotonin and noradrenaline selectively) and the development of TRD is anhedonia. We covered this in more detail in the article on pramipexole in TRD. 

Anhedonia is an interest-activity symptom dimension that has been associated with dopamine dysfunction in the basal ganglia and impaired cortical-striatal reward circuitry.

Pramipexole is beneficial in depression due to pramipexole-induced stimulation of postsynaptic dopamine D2 receptors which highlights the role of the dopamine system in depression.

WHAT DID THE PHYSICAL EXAMINATION SHOW?

A physical examination is necessary in cases of depression as abnormalities can point toward underlying medical causes. The physical examination revealed –

1. Abnormal Luria (Fist-edge-palm)
2. Mild cogwheel rigidity in both upper limbs

Video of Abnormal Luria

Learning Point 3 –

Luria is a useful screening test for frontal lobe function and tests set shifting. It is another way of validating the CTSC loop linked to the Dorsolateral Prefrontal Cortex (DLPFC) which is the seat of executive function.

The DLPFC is linked to the striatal complex and reduction of dopamine in this area can produce cogwheel rigidity and executive dysfunction.

Similarly antipsychotics can lead to parkinsonian side effects by blocking dopamine in the nigrostriatal area as shown in the video below.

Learn more about the importance of frontal lobe examination and ther tests that can be used to examine the frontal lobe. 

NEUROIMAGING

An MRI was therefore carried out for the following reasons –

1. Executive dysfunction
2. Late-onset depression
3. Cogwheel rigidity – indicative of sub-cortical involvement.
4. To rule out vascular subcortical depression, i.e. presence of white matter hyperintensities which are associated with a more resistant form of depression and cognitive dysfunction.

The MRI showed –

Two foci of white matter hyperintensities, one in the deep white matter of the left parietal lobe as a likely area of previous ischaemia and mild advanced cerebral atrophy.

Example of White Matter Hyperintensities

Learning Point 4 –

Magnetic resonance imaging studies examining elderly patients with depression have identified an increase in hyperintensities in the subcortical white and deep gray matter. White matter hyperintensities (WMHs) have been divided into 2 types: those adjacent to the ventricular system [periventricular hyperintensities (PVHs)] and those separate from the ventricles in the deep white matter (deep white matter hyperintensities [DWMHs]).

Lesions appear most strongly linked to depression when they involve frontal-subcortical circuits that reciprocally link prefrontal areas (the dorsolateral prefrontal cortex [DLPFC] and the anterior cingulate cortex [ACC]) to the basal ganglia).

White matter hyperintensities predict an increased risk of stroke, dementia, and death. Therefore white matter hyperintensities indicate an increased risk of cerebrovascular events when identified as part of diagnostic investigations, and support their use as an intermediate marker in a research setting. Their discovery should prompt detailed screening for risk factors of stroke and dementia. (Debette, 2010)

You can read more about the clinical significance of WMH’s here. 

WHAT IS GOING ON?

There is a range of possibilities for this presentation. But the ones to prioritise are –

1. Rule out an organic cause (Blood tests and MRI)
2. High-dose Sertraline can result in significant emotional blunting. (Activation of Serotonin can reduce DA and NA in the PFC via 5HT2A and 5HT2C activation of GABA neurones which in turn reduce dopamine).
3. Dopamine dysfunction in the prefrontal circuits linked to possible structural atrophy may be responsible for the onset of depressive symptoms.

Learn more

10 point guide to a medical evaluation in depression

Emotional blunting with SSRIs

MANAGEMENT PLAN

1. Emotional blunting was ruled out by reducing the dose of Sertraline. The patient did not respond.
2. Agomelatine was used in conjunction with Sertraline to increase Dopamine in the PFC.
3. Vit B 12 deficiency was corrected. (B12 is a cofactor in the synthesis of neurotransmitters such as serotonin and dopamine. Thus B12 deficiency can lead to psychiatric disorders).

Learning point 5 –

SNRI’s (e.g. Duloxetine, High dose Venlafaxine) can increase NA and DA in the PFC but increase the risk of Serotonin Syndrome in combination with Sertraline.

Bupropion can also increase dopamine selectively. Mirtazapine above doses of 30 mg can also be used to increase NE and DA in the PFC via the Alpha-2 receptor antagonism and 5HT2C antagonism. 

Agomelatine increases dopamine in the PFC by blocking the 5HT2C receptor without any concurrent serotonin increase.

Augmentation with Agomelatine is a valid treatment strategy creating a broad spectrum antidepressant combination. [Potměšil P, 2019]

A successful combination of agomelatine was reported after adjunctive use of agomelatine combined with clomipramine, escitalopram, and venlafaxine in patients with major depression or obsessive–compulsive disorder. Moreover, bupropion or moclobemide augmentation with agomelatine in patients with major depressive disorder led to a significant improvement.

Learn more about the mechanism of action of 21 commonly used antidepressants.

RESULT

The patient experienced full remission of her depressive symptoms which has been maintained at six months.

She is working full-time at her accountancy firm. Her husband corroborates the information.

Learning Summary –

1. You can address depression better by deconstructing symptoms and connecting them to structural circuits and then thinking about the neurotransmitters involved.
2. Anhedonia may be linked specifically to dopamine pathways and may need dopaminergic agents for improvement.
3. Vascular (sub-cortical) depression is a distinct entity and requires close collaboration with the GP / physician to manage vascular risk factors.
4. Address organic contributors to the depression
5. Use psychopharmacological modulation based on the understanding of receptors to avoid a trial and error approach.
6. Use our learning tool to understand the mechanisms of action and side effects of antidepressants. The tool also helps you to target appropriate antidepressants to patient symptoms.

QUIZ