Kindling as a model for affective disorders
Ralph Kupka MD, Altrecht
Institute for Mental Health Care and University Medical Centre, Utrecht, The Netherlands. Supported
in part by the Theodore and Vada Stanley Foundation.
Review
Unipolar depression and manic-depressive illness
are psychiatric disorders of a highly recurrent nature. Although it is difficult to make
predictions in individual cases, as the course of mood disorders shows considerable
variation, a general tendency of worsening over the years is reported by many studies from
the prepharmacological era, and from the pharmacological era in nonresponders (reviewed by
Post et al. 2000). From many studies a decreasing interval between episodes is most
obvious in the initial phase of illness.
The kindling model of recurrence in affective
disorders gives a conceptual framework to some of the phenomena of illness initiation and
progression. Kindling has originally been developed as an animal model for
epileptogenesis. Its application to recurrent affective disorders was inspired by temporal
and developmental similarities between the clinical course of affective disorders
and that of seizure disorders.
For a proper understanding it is important to
emphasize that kindling is a non-homologous model when applied to psychiatric disorders,
and that it does not imply that seizure disorders and affective disorders are
behaviourally homologous, or have common causes or pathophysiologies. It therefore follows
that the kindling model does also not give a direct explanation for the efficacy of
anticonvulsants in affective disorders. Despite these limitations, the kindling and
behavioural sensitisation models offer hypotheses of how affective disorders may evolve as
a function of each subsequent episode, and the concomitant treatment implications.
Kindling is the progressive induction of seizure
activity by repeated and appropriately spaced, subthreshold stimuli, up to a stage of
spontaneous seizures. It is accompanied by long-lasting, and possibly even permanent,
functional and structural changes in the brain, and can be modified by pharmacological
intervention. The efficacy of anticonvulsants with regard to kindled seizures depends on
the nature of the inducing stimulus, the phase of kindling development, and the type and
administration of the drug. These characteristics are important for the understanding of
kindling as a model for illness progression in affective disorders and its treatment.
According to the kindling analogy, in a
genetically predisposed individual certain types of stressors, repetitively experienced in
a vulnerable period and environment, will lead to mood symptoms of increasing intensity
and duration until a full-blown depressive or manic episode occurs. This process is
accompanied by functional and structural changes in the brain systems involved, thereby
increasing the vulnerability for a next episode. Thus stress not only precipitates a given
mood episode in a genetically predisposed individual, but also adds to the subsequent
vulnerability for new episodes by altering the underlying neurobiological mechanisms. In
further addition to this stress sensitisation, it is postulated that every new episode
leaves a trace and thus contributes to the individuals’ vulnerability, a mechanism
which has been referred to as episode sensitisation.
Post and Weiss postulated a theory of illness
cyclicity in which primary pathological (proconvulsant) processes of a long-lasting nature
are temporarily counter-balanced by transient secondary compensatory (anticonvulsant)
mechanisms, which are inherent to an illness episode. This implies that each episode
induces factors that facilitate its own remission, and a certain period of well-being
afterwards, until this adaptation fades away and the pathological drive of the underlying
illness leads to the next episode.
Clinical studies with relevance to the
kindling hypothesis
It is tempting to associate the efficacy of
anticonvulsants in bipolar affective disorder with the kindling hypothesis. It must be
clear however, that the kindling paradigm is not an animal model to test the
mood-stabilizing efficacy of any drug. The mere fact that anticonvulsants which are
effective in mood disorders, also can interfere with the development of kindling or its
manifestations, does not imply that these antikindling properties predict antimanic,
antidepressive or mood-stabilizing efficacy.
The rationale provided by the kindling model is
that the underlying neurobiology of the illness changes with each new mood episode, and,
as a consequence, a different treatent approach is required as the illness evolves.
In conclusion, the kindling and sensitisation
models, despite their limitations, provide a conceptual framework which may contribute to
the understanding of important aspects of the longitudinal course of recurrent affective
disorders. These include illness progression and cyclicity, sensitisation to environmental
stressors, differential pharmacologic responsivity at various stages of illness evolution,
and the issues of tolerance and treatment-discontinuation-induced refractoriness. Given
the broad variety of illness patterns, kindling-like mechanisms underlying these phenomena
probably apply to a subgroup of patients in the spectrum of affective disorders.
Ultimately, it is the model's heuristic value and predictive validity that will determine
its utility.
Recommended references
McNamara, J.O., and Wada, J.A. (1997). Kindling
model. In: Engel, J. and Pedley, T.A. (Eds), Epilepsy: A Comprehensive Textbook,
Lippincott Raven Publishers, Philadelphia, pp. 419-425.
Post, R.M. (1992). Transduction of psychosocial
stress into the neurobiology of recurrent affective disorder. American Journal of
Psychiatry, 149, 999-1010.
Post, R.M., Rubinow, D.R., and Ballenger, J.C.
(1986). Conditioning and sensitisation in the longitudinal course of affective illness.
British Journal of Psychiatry;149, 191-201.
Post, R.M., Speer, A.M., Leverich, G.S., Wiess,
S.R.B., and Ketter, T.A. (2000). Predictive validity of the sensitization and kindling
hypotheses. In: Soares, J.C., and Gershon, S. (Eds), Bipolar disorders. Basic Mechanisms
and Therapeutic Implications. Marcel Dekker, Inc., New York, pp. 387-432.
Weiss, S.R.B., and Post, R.M. (1994). Caveats in
the use of the kindling model of affective disorders. Toxicology and Industrial Health,
10, 421-447.
27-10-2001
| Ralph Kupka - Altrecht Institute for Mental Health Care; University Medical Centre, Utrecht, The Netherlands and Stanley Foundation Bipolar Network - received his medical and psychiatric training at the Academic Medical Centre of the University of Amsterdam, The Netherlands, and subsequently became a lecturer at the same medical faculty. Since 1995 he has worked as a clinical and research psychiatrist at the University Medical Centre of Utrecht, The Netherlands and the Altrecht Institute for Mental Health Care, a large psychiatric hospital and community mental health centre in the same city. Dr Kupka participates as a principle investigator in the Stanley Foundation Bipolar Network, a collaboration of academic centres in the USA, The Netherlands and Germany, headed by Robert Post at the National Institutes for Mental Health. This multi-site research programme evaluates the long-term course and treatment outcome of bipolar illness, and carries out clinical trials of various established and potential mood stabilising medications. Dr Kupka has a special interest in rapid cycling relating to altered endocrine and immune function. |