Changes in the brain linked to major depressive disorder

Although major depressive disorder (MDD) is often thought about as one disease, it is clear there are many subtypes, said Professor Knudsen, who highlighted current understanding of the variety of biological mechanisms linked to MDD, including:

Major depressive disorder is a heterogeneous disease with many combinations of symptoms

• Altered neurotransmission involves the monoamines and the glutaminergic and GABAergic systems. The monoamine theory for MDD, based on a lack of serotonin (and to some extent noradrenaline) has prevailed many years, said Professor Knudsen, but now the glutamatergic and GABAergic systems are also considered to play an important role.¹
   
• The stress response involving the hypothalamic-pituitary-adrenal axis and neurosteroids, with changes in neuroactive steroid signalling particularly affecting the GABAergic system.^1,2

Altered neurotransmission in major depressive disorder involves the monoaminergic, glutamatergic, and GABAergic systems

• Impaired neuroplasticity. Normally the brain adapts to what it learns leading to changes in the brain associated with increased synapses or production of new neurons in the hippocampal area, but this behaviour is impaired in MDD.¹
• Neuroinflammation¹

In addition, different brain regions interact to form a neural network providing connectivity between different brain regions, said Professor Knudsen. Some of these networks play a role in MDD, for example, the default mode network.³

The default mode network plays a role in major depressive disorder

Anatomic changes in the brain in MDD include:

• Impaired neuroplasticity and neurogenesis, glial cell mediated damage and neuroinflammation microscopically. Impaired neuroplasticity and neurogenesis are evident on molecular imaging as decreased synaptogenesis¹
• A variety of grey and white matter changes, most notably hippocampal atrophy, macroscopically¹

Hippocampal atrophy is a notable anatomic change in major depressive disorder

Impaired adaptive signalling results in the core symptoms of major depressive disorder

A video was played during Professor Knudsen’s presentation to explain adaptive signalling in the interconnected neuronal networks in the brain. Adaptive signalling allows the brain to respond and adapt to stimuli, seeking to restore homeostasis through excitatory, inhibitory, and modulatory signalling.³

• GABA and glutamate are the primary inhibitory and excitatory neurotransmitters, respectively
• The less prevalent monoaminergic neurons are modulatory

The GABA/glutamate balance is critical for all neuronal network functions including regulation of monoaminergic pathways.

The GABA/glutamate balance regulates monoaminergic pathways

Professor Knudsen explained impaired adaptive signalling (i.e. the impaired ability for the brain to respond and adapt to stimuli):

• Is associated with altered neurotransmission and changes in neuroactive steroid signalling⁴

• Results in dysregulation of neuronal networks,⁵ which in turn are linked to the core symptoms of major depressive disorder (MDD) — depressed mood, anhedonia, feelings of worthlessness or excessive guilt, suicidality, and sleep difficulties⁶  

 The core symptoms of major depressive disorder are linked to impaired adaptive signalling

Professor Knudsen highlighted that in the future the identification of biomarkers involved in these mechanisms will enable patient stratification into different subtypes and facilitate a precision medicine approach with more individualised treatment.