Part I: Mood and Neurological Disorders
The treatment of mood and neurological disorders has rapidly evolved with the development of increasingly targeted small molecules. For many with mood disorders, notably major depressive disorder, or degenerative disorders such as Alzheimer’s disease or Parkinson’s disease, the development of small molecule therapies that narrowly impact relevant brain pathways has offered patients better quality of life and symptom relief with fewer adverse events.

Major Depressive Disorder
The monoamine theory of depression guided research and development toward small molecules that correct imbalances of neurotransmitters. When first developed, monoamine oxidase inhibitors (MAOI) showed promise to treat depression. However, because they increase levels of norepinephrine, serotonin, and dopamine (centrally and peripherally), they required dietary restrictions and often caused adverse events.¹¹³

MAO-A inhibitors have applications in depression, and MAO-B inhibitors in the treatment of Parkinson’s disease.¹¹⁴

• MAO-A inhibitors: clorgyline, moclobemide, brofaromine, phenelzine,
• MAO-B inhibitors: selegiline, rasagiline, ladostigil, tranylcypromine, isatin, safinamide, menadione

In part because of adverse events, small molecules for the treatment of depression evolved to selectively target single neurotransmitters (e.g., selective serotonin reuptake inhibitors [SSRI]), or two neurotransmitters (e.g., duloxetine, a selective serotonin and norepinephrine [SNRI] reuptake inhibitor). Further reductions in side effects have been achieved by cleaving the isomers of marketed amine-modifying treatments (e.g., desvenlafaxine, escitalopram).

Alzheimer’s Disease
Dr. Emil Kraepelin named Alzheimer ’s disease (AD) in 1910 after Alois Alzheimer, the first physician to describe a patient suffering from cognitive decline including memory loss and paranoia.¹¹⁵ After the patient’s death, Alzheimer noticed degeneration of her brain and abnormal deposits around brain cells.¹¹⁶ The first drugs to treat AD increased central acetylcholine in the brain, a neurotransmitter that plays a key role in learning and memory. Subsequently, memantine, a drug regulating the neurotransmitter glutamate, was introduced and prescribed individually and along with drugs targeting acetylcholine.¹¹⁷

Existing treatments for AD mask cognitive decline, but do not treat the underlying causes. AD research is now focused on small molecules that impact the characteristic plaques and tangles of the AD brain. Current research efforts target a spectrum on mechanisms of action underlying AD brain pathology.

• Beta-secretase inhibition¹¹⁸ by antibodies have met with poor results in clinical trials, but the small molecule verubecestat (MK-8931) is in Phase III.^119,120,121
• Amyloid-beta signal modulators:
  • Bryostatin — natural product protein kinase C agonist, enhances synaptogenesis¹²²
  • Rolipram — proteasome activator via cAMP-protein kinase A signaling Phosphodiesterase-4 inhibitor¹²³
  • Sildenafil — Phosphodiesterase-5 inhibitor, elevates cGMP and reduces tau hyperphosphorylation^124,125
• Prevention of Tau oligomerization
  • Methylthioninium chloride¹²⁶
  • ELND005 (scyllo-inositol, Phase II clinical trial)¹²⁷

Parkinson’s Disease
As a result of the development and advancement of small molecules, patients with Parkinson’s disease (PD) have many more treatment options than the venesection and skin blistering first advocated by Parkinson in the early 19^th century.¹²⁸ Belladonna alkaloids, later understood to act on both cholinergic and dopaminergic systems in the striatum, were the first well-established treatments for Parkinson’s disease.¹²⁹ The definitive link between striatal dopamine loss and Parkinson’s disease symptoms, coupled with the confirmation of levodopa as dopamine precursor, ushered in human clinical trials for levodopa in Parkinson’s disease patients in 1961.¹³⁰ Levodopa has been the backbone treatment for Parkinson’s disease since human clinical trials confirmed its efficacy. However, because Parkinson’s disease robs the brain of the dopamine neurons required for L-dopa to improve symptoms, L-dopa efficacy eventually wears off. This enhanced understanding of PD disease course has led to the development of small molecules that work synergistically with L-dopa, and that target additional neurotransmitter systems.

Small molecules approved to treat PD:

• Dopamine agonists: ropinirole, pramipexole, rotigotine
• NMDA glutamate receptor antagonist: amantadine
• MAO-B inhibitors: selegiline, rasagiline (improved side effect profile of metabolites)
• COMT inhibitors: tolcapone, entacapone

Summary
Small molecules have greatly advanced the effectiveness with which clinicians treat diseases of the brain. Small molecules that penetrate the blood-brain barrier represented a leap forward in therapeutic developments for psychological and neurological disease. Additionally, drugs that discriminately act at neuronal versus peripheral sites typically produce fewer treatment-related adverse events.