Indian J. Psychiat. (1982), 24(4), 329—337 PINEAL RESPONSE TO LITHIUM1 S. PARVATHI DEVI* A. VENKOBA RAO> PINEAL FUNCTION AND BEHAVIOUR—A until Crowther demonstrated from his REVIEW autopsy studies that pineal calcification The pineal gland in ma.i is an active had nothing to do with mental derange­ endocrine gland throughout life (Wurtman ment. et al., 1964 ; Tapp & Huxley, 1972 ; Interest in the pineal gland lay dormant Cardinali, 1974 ; Reiter et al., 1975 ; Reiter, and the gland was relegated to be a ves- 1978). It elaborates several hormones with tigeal organ until the endocrine nature precise rhythmicity. The chronobiological of the gland was suggested following des­ aspects of the mammalian pineal gland have criptions of pineal tumours associated with been clearly brought out by Reiler (198!) precocious puberty (Kitay, 1954). The defining the circadian rhythms in indole idea of a special relation of pineal gland to metabolism within the pineal of mammals. mind was revived in reports of experiments The two major classes of pineal hormones— with pineal extracts in the treatment of pineal indoles (melatonin, serotonin and schizophrenia (Becker, 1920 ; Eldered et the tryptophols) and the polypeptides are al., 196U; Kitay & Altschule, 1954). The known to influence several physiological isolation and characterisation of the pineal systems including the central nervous system hormone melatonin was a turning point (Cardinali, 1974 and Anton Tay, 1974). in pineal research (Lerner et al., 1958). The association of pineal gland with be­ Since then the pineal gland has been a haviour and mental illness can be traced to focus of intense scientific enquiry revealing Alexandrian school of thought (Herophilus it to be an endocrine gland capable of c. 300 B.C.). that the pineal is a sphincter affecting brain and behaviour. which regulates the flow of thought. Among the early observations on the Descartes (1650) located the soul, the influence of pineal gland on the brain are origin of all thought in the pineal gland these of Quay (1965) on the inability of (quoted in Hunter and Macalpine, 1963). pinealectomised rats to maintain their cere­ The first recorded post mortem at Bethletn bral potassium content. A slowing of brain Hospital by Thomas Allen in 1976 revealed maturation, particularly myelination was that the pineal gland was "turned into a reported after pinealcetomy in animals bladder of water" (Hunter and Macal­ (Relkin et al., 1973 ; Relkin & Schneck, pine, 1963). King (1686) observed that a 1975). mentally deranged patient, had a petrified Pinealectomy is accompanied by a pineal. Gunz (1753) suggested that con­ general increase in neural excitability (Nir cretions of pineal might be the cause of et al., 1969) and in stimulus-induced hippo- mania. This was supported by Morgagni campal potentials with convulsive patterns (1769) and Arnold (1786). Assertions of a (Bindoni and Rizzo, 1965). Frank con­ link between the pineal and insanity con­ vulsions have been noted after pinealectomy tinued to appear in the eighteenth century in previously thyroparathyroidectomised ani- 1 The Authors would like to name the response as "Tilak Effect". 2 Director & Professor, Institute of Physiology, Madurai Medical College, Madurai-625020. 3 Professor & Head, Institute of Psychiatry, Madurai Medical College & Govt. Rajaji Hospital, Madurai- * 625020, 330 S. PARVATHI DEVI & A. VENKOBA RAO mals (Reiter and Morgan, 1972 ; Reiter rescence in the rat pineal gland, signifying et al., 1972a). The convulsions result from hyper activity (Parvathi Devi et al., 1978). changes in brain electrolytes and nore­ Above all these facts, it has been found pinephrine content (Reiter et al., 1972 ; that plasma melatonin concentrations are Reiter, 1977). high at night and low or absent during the Administration of pineal extracts in­ day both in animals and men (Rollag & duces EEG activation (Quay and Renzoni, Niswender, 1976 ; Arendt et al., 1977 ; 1963 ; Roldan and Anton-Tay, 1968). Smith et al., 1977 ; Kennaway et al., 1977). Melatonin has powerful sedative effects In several recent studies of the temporal on animals (Marceynski et al., 1964 ; organization of melatonin concentrations Barchas et al., 1967 ; Hishikawa et al., during 24-hour periods in normal men, 1969). In human volunteers and in epi­ Weinberg et al. and Weitzman et al. have leptics receiving melatonin an increase in shown that although melatonin values are alpha activity, EEG synchronisaiton and significantly higher at night during sleep, shep, dreams, REM cycles, visual imageries episodic secretion exists during the waking and feelings of well-being have been ob­ daytime period (Weinberg et al., 1973 ; served (Anton Tay, 1971 ; 1972 ; Cramer and Weitzman et al., 1978). et al., 1976). In epileptics the paroxysmal Lewy et al., (1979), who used a new discharges were suppressed by injections mass spectroscopic assay, have found that of melatonin (Anton-Tay et al., 1971). the nocturnal secretion of melatonin from Therapeutic benefits have been claimed the pineal gland was substantially reduced with melatonin as an oral anticonvulsant during depressive phases compared to manic (Anton Tay, 1974). phases in bipolar cases. Since beta-adr­ A well substantiated behavioural effect energic and serotonergic mechanisms me­ of melatonin is its ability to induce sleep diate melatonin secretion, these observations (Barchas et al., 1967; Marczynski et al., could implicate disturbances in these neuro­ 1964). Melatonin decreases the latency of transmitter systems. sleep onset, of stages 3 and 4 and of REM Recent studies suggest that certain sleep. The pattern of sleep induced strik­ depressed patients may have an altered ingly resembles natural sleep (Cramer et biological rhythm. Alterations have been al., 1974, 1976). It facilitates barbiturate found in the sleep waking pattern timing of induced sleep (Martini, 1971). Koella activity levels, diurnal mood variation and (1969) has suggested that normal sleep in the daily secretion of pituitary hormones may involve leakage of pineal hormones as well as in other biological variables and their hyper-synchronising action via (Hawkins & Mendels, 1966 ; and Sachar, the area postrema, tractus solitarius and 1976). Since derangements of biological upper brainstem. Pineal arginine vasotocin rhythm function have been linked with (AVT) is reported to suppress REM sleep depression we considered it of interest to (Pavel et al., 1977). investigate the temporal organization of Following pinealectomy, dissociation melatonin secretion in patients with uni­ develops between the nycthemeral varia­ polar and bipolar depression. The likely tions of REM and slow-wave sleep. REM central nervous influence on melatonin sleep decreases during the high phase of secretion in man, its possible reflection of the cycle and increases during the dark brain beta-receptor sensitivity (Hanssen, phase (Anton Tay, 1972). In our studies, 1977) and the resemblance of its annual it was observed that following a 48-hour secretion pattern to that of hospital admis­ selective REM sleep deprivation, there sion for depression (Eastwood and was an increase in the NE and 5-HT fluo­ Peacocke, 1976) lead to the suggestion that PINEAL RESPONSE TO LITHIUM 331 the study of rhythmic human melatonin less abundant in the earth's crust than secretion may prove to be of importance in Sodium and Potassium it is known to be diagnostic, prophylactic and therapeutic far more abundant than silver and Gold. psychiatry. Of major importance in psy­ Industrial and technological (textiles, cera­ chiatry are schizophrenia and manic-de- mics, electronics, batteries, air-conditioners, pressive disease which also for other reasons enamel and glasses, aluminium) applica­ have been linked to a possible disturbance tions of Lithium exceed diose of its medical in pineal function (Allschule, 1975 ; and use. Carman et al., 1976). Watterberg, (1978) Lithium was introduced to Medicine pointing disturbances in melatonin meta­ by Lipowitz in 1841 and by Garrod in bolism in schizophrenic and depressed 1859 and to Psychiatry as an antimanic patients and has suggested the possible use agent by Cade in 1949. After a period of of melatonin excretion pattern as a pre­ lull, the Aarhus group of investigators in dictive tool in the evaluation and outcome Denmark led by Schou added considerable when treating depressed patients with sleep knowledge of i(s use to make lithium one deprivation therapy. Mendlewicz et al. of the most important rediscoveries in (1980) noting the 24 hour pattern of plasma psychiatric therapies. melatonin in depressed patients before and The exact mechanism of action of after treatment indicated that the nocturnal lithium is not yet satisfactorily known. melatonin increase found in normal sub­ In the earlier days of its application, atten­ jects was essentially absent in 3 of the 4 tion was directed to its effects upon electro­ depressed patients suggesting an altered lyte balance. Lithium can never act as pineal rhythm. The functional significance a substrate for sodium though it replaces of the pineal in behaviour becomes very it and hence a failure in sodium pump evident. mechanism occurs. The neuronal mem­ brane is unable to maintain the polarization LITHIUM—ITS MODES OF ACTION—A and conduct action potentials. However REVIEW this is not likely in the clinical concen­ Lithium sulfate was identified in 1817 tration of lithium in the blood. It was also by Arvedson, a young Swedish student advanced that lithium might correct a