Global Journal of Medical Research, A: Neurology & Nervous System, Volume 23 Issue 3

believe that each psychiatric syndrome has its own unique biological underpinnings [10]. The need to better understand these disorders has become imperative, as the effectiveness of treatment is lagging far behind the escalating mental health crisis. Thus far, the only psychiatric disorder for which there has been a consensus opinion is clinical depression, for which the monoamine hypothesis has guided the use of antidepressants for more than fifty years [11]. Over the past decade, however, even this hypothesis has been called into question because of its failure to explain several important observations. First, it fails to explain how antidepressants can be effective in the treatment of psychiatric disorders other than clinical depression [12]; second, it fails to explain why a depletion of serotonin precursors does not produce depression symptoms in healthy subjects [13]; third, it fails to explain why antidepressants can sometimes cause a paradoxical worsening or cycling of symptoms [14-18]; and fourth, it fails to explain how the putative abnormalities in monoamine transmission actually translate into depressive symptomatology [19]. However, an emerging hypothesis offers answers to these questions and supersedes the monoamine hypothesis by providing the first neuropsychiatric explanation for a wide range of psychiatric disorders and related clinical observations. According to the multi-circuit neuronal hyperexcitability (MCNH) hypothesis, psychiatric symptoms, irrespective of their symptom-based diagnosis, are caused by pathological hyperactivity in the associated neuronal circuits [20]. Thus, for example, pathological hyperactivity in anxiety circuits causes elevated and persistent feelings of anxiety; pathological hyperactivity in depressive circuits causes elevated and persistent feelings of depression; and pathological hyperactivity in cognitive circuits causes racing thoughts and obsessive thinking [20]. The most common cause of this hyperactivity is thought to be cognitive-emotional stress, as tension in the mind, like stones being thrown at a beehive, has an agitating effect on the brain. According to the MCNH hypothesis, this agitating effect is abnormally amplified when the neurons of the brain, like irritable bees, are inherently hyperexcitable [19]. This would not only explain many observations that the monoamine hypothesis does not [11, 21], but it would also incorporate the effects of brain structure [22], brain physiology [19, 20], brain circuitry [20, 23], and mind- brain dynamics [19] to explain virtually every phenomenon that has been observed clinically in psychology and psychiatry [22-27]. It would also explain why there is so much overlap between symptom-based psychiatric diagnoses [22], and why the same medications can often be used to treat multiple psychiatric syndromes [28, 29]. III. T oward a P athology-based A pproach to T reatment What the MCNH hypothesis suggests is that a wide range of psychiatric disorders, including generalized anxiety disorder, major depressive disorder, bipolar disorder, obsessive-compulsive disorder, post- traumatic stress disorder, attention deficit hyperactivity disorder, and schizophrenia, could be treated by simply reducing the excitability of the neurological system. Although the use of anticonvulsants had traditionally been relegated to the treatment of bipolar disorder [30, 31], the added ability of these drugs to treat a wide range of psychiatric disorders is illustrated by three significant advances in psychiatry: 1) the establishment of bipolar spectrum disorders as a dimensional diagnosis [7, 8]; 2) the recognition that anticonvulsants are the drugs of choice for all disorders in the bipolar spectrum [32]; and 3) the rapid antidepressant effects of ketamine [33, 34] and zuranolone [35-37], both of which have potent brain-calming effects. Still, that raises the question of why it has taken so long to recognize the broad applicability of anticonvulsants. The answer lies in the flood of excitement that was created when the antidepressant effect was serendipitously discovered in the 1950s. An Associated Press release from Staten Island’s Seaview Hospital, where the mood-elevating effect of anti-tuberculin drugs was first recognized, captured a telling scene: patients dancing in celebratory mood [38]. Some of the patients, who were still in quarantine for tuberculosis, were feeling so good emotionally that they wanted to leave the hospital against medical advice. In other words, the antidepressant effect of isoniazid was not just normalizing mood; it was elevating mood to the point of affecting judgement. Nonetheless, the impressiveness of the effect and subsequent acceptance of the monoamine hypothesis as a neurochemical explanation for the effect caused it to be heralded as a medical breakthrough. Subsequently, clinicians became strongly entrained to prescribe antidepressants for almost any patient who presented with depressive symptomatology. However, consistent with the idea that antidepressants were causing a subtle, mood-related distortion of judgment, their use was also found to increase the risk of switching from depression to mania in some patients [15-18]. Based on evidence that this risk was greatest in patients with bipolar disorder [14- 18], concerted efforts were made to distinguish bipolar disorder from unipolar depression [7, 39-41]. The problem is that these two disorders can be indistinguishable, at least until the first manic phase of bipolar disorder occurs. Even then, the diagnosis can be delayed because mania itself often evades detection. The difficulty of making an accurate diagnosis is illustrated by the fact that the average patient with bipolar disorder is misdiagnosed with unipolar 26 Year 2023 Global Journal of Medical Research Volume XXIII Issue III Version I ( D ) A © 2023 Global Journals A Precision Medicine Approach to the Treatment of Psychiatric Disorders