A SPECULATIVE MODEL OF AFFECTIVE-ILLNESS CYCLICITY BASED ON PATTERNS OF DRUG TOLERANCE OBSERVED IN AMYGDALA-KINDLED SEIZURES

In this article, we discuss molecular mechanisms involved in the evolu tion of amygdala kindling and the episodic loss of response to pharmac ological treatments during tolerance development. These phenomena allo w us to consider how similar principles (in different neurochemical sy stems) could account for illness progression, cyclicity, and drug tole rance in affective disorders. We describe the phenomenon of amygdala-k indled seizures episodically breaking through effective daily pharmaco therapy with carbamazepine and valproate, suggesting that these observ ations could reflect the balance of pathological vs compensatory illne ss-induced changes in gene expression. Under certain circumstances, am ygdala-kindled animals that were initially drug responsive can develop highly individualized patterns of seizure breakthroughs progressing t oward a complete loss of drug efficacy. This initial drug efficacy may reflect the combination of drug-related exogenous neurochemical mecha nisms and illness-induced endogenous compensatory mechanisms. However, we postulate that when seizures are inhibited, the endogenous illness -induced adaptations dissipate (the ''time-off seizure'' effect), lead ing to the re-emergence of seizures, a re-induction of a new, but dimi nished, set of endogenous compensatory mechanisms, and a temporary per iod of renewed drug efficacy. As this pattern repeats, an intermittent or cyclic response to the anticonvulsant treatment emerges, leading t oward complete drug tolerance. We also postulate that the cyclic patte rn accelerates over time because of both the failure of robust illness -induced endogenous adaptations to emerge and the progression in patho physiological mechanisms (mediated by long-lasting changes in gene exp ression and their downstream consequences) as a result of repeated occ urrences of seizures. In this seizure model, this pattern can be inhib ited and drug responsivity can be temporarily reinstated by several ma nipulations, including lowering illness drive (decreasing the stimulat ion current), increasing drug dosage, switching to a new drug that doe s not show crosstolerance to the original medication, or temporarily d iscontinuing treatment, allowing the illness to re-emerge in an unmedi cated animal. Each of these variables is discussed in relation to the potential relevance to the emergence, progression, and suppression of individual patterns of episodic cyclicity in the recurrent affective d isorders. A variety of clinical studies are outlined that specifically test the hypotheses derived from this formulation. Data from animal s tudies suggest that illness cyclicity can develop from the relative ra tio between primary pathological processes and secondary endogenous ad aptations (assisted by exogenous medications). If this proposition is verified, it further suggests that illness cyclicity is inherent to th e neurobiological processes of episode emergence and amelioration, and one does not need to postulate a separate defect in the biological cl ock. The formulation predicts that early and aggressive long-term inte rventions may be optimal in order to prevent illness emergence and pro gression and its associated accumulating neurobiological vulnerability factors.