The ‘cerebral diabetes’ paradigm for unipolar depression

Medical Hypotheses MPdiCd Hypothrws (lY93) 41. 3Y14llX @ Longman GroupUK Ltd 1993

The ‘Cerebral Diabetes’ Paradigm for Unipolar Depression J. C. NEWMAN

(DECEASED)

Lakeview House, Shellharbour NS W 2529, A us tralja

and R. J. HOLDEN

Hospital, lllawarra Area Health Service, l?O. Box 52, Shellharbour

Square,

Abstract-Unipolar depression, alcoholism and suicide have become more common over the past decades. Genetic studies have attempted to link (bipolar) affective disorder to the short arm of chromosome 11 (where the loci for insulin, insulin growth factor (IGF), tyrosine hydroxylase (TH) and h-ras-oncogene are located) but these have failed. Since TH and the insulin receptor require phosphorylation by protein kinases, then a defect of the h-ras-oncogene or its products (~21) could disorder both these systems and compromise catecholaminergic transmission in neurones and energy flow in glial cells. This could lead not only to a predisposition to depression (‘trait markers’) but to neurotoxic damage, predisposed by inadequate cytosol Mg2+ levels or hypometabolism. Tyrosine, tryptophan and phenylalanine hydroxylases all require tetrahydrobiopterin (BH4) which allosterically regulates its own activity as well as that of these enzymes. Anything which impairs this cofactor could lead to over-l depression in predisposed individuals, and the heterocyclic amines are being increasingly implicated. These substances are derived from fried and broiled meats, azo food dyes, soft drinks and hard candies, but particularly from cigarette and petroleum fumes. The heterocyclic amines can inhibit aromatic-I-amino-acid-decarboxylase (AADC) as well as the hydroxylases reversibly, but BH4 is inlhibited noncompetitively. Thus, susceptible individuals (those with inherited defective protein kinase phosphorylation) might be ‘tipped over’ by chronic exposure to these neurotoxins. The rising incidence of unipolar depression-associated morbidity could be significantly linked to increasing levels of heterocyclic amines in the developed nations.

A ‘trait marker’ is a biologic measure which remains constant with time or treatment. It is a marker for soNme underlying genetic or biochemical defect. The ‘tyramine excretion test’ originally described by Sandler et al in 1975 (1) seems to relate specifically to unipolar depression, while a different trait-marker, the growth-hormone response to a clonidine challenge,

may reflect an index of vulnerability to bipolar disorder (2, 3). Quantifying the amount of sulphoconjugated tyramine in urine (over a 3 h collection time) is a simple and cost-effective means for diagnosing depression within specific populations, such as migraine sufferers or pregnant women (4, 5). However, its basis has

Date received 5 February 1993 Date accepted24 June 1993

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never been understood, and this has led to scepticism regarding its utility (6). Over the past 17 years, Sandler and others have consistently described an association between urinary tyramine sulphate output and depression (7-II), and more recently, the test has been said to discriminate between unipolar and bipolar types of depression. Other studies have shown that the relatives of depressed patients themselves had a reduced tyramine excretion in over half the cases studied (12), and that this excretion defect persisted in spite of treatment (13). A proper understanding of the tyramine test demands a clear understanding of the respective path-

ways of tyramine synthesis in the gut, kidney and brain, For instance, most urinary tyramine seems to be derived from plasma tyrosine, yet most conjugated tyramine (following an oral challenge) comes from the small intestine via leucocyte and platelet phenolsulphotransferases (14, 15). Brain tyramine is derived from phenylethylamine (which crosses the bloodbrain-barrier), from tyrosine, and from the catabolism of dopamine (16, 17). Finally, brain tyramine is primarily catabolised by MAO-B and PST-M (18) and is excreted chiefly as acid derivatives in the urine. Figure 1 outlines these separate pathways.

ORAL TYRAMINE CHALLENGE

f gut PST errcx

PH = phenylalanine hydroxylase MAO = monoamine oxidase PST = phenylsulphotransferase AADC = aromatic-L-amino acid decarboxylase TH = tyrosine hydroxylase HB4 = ztrahydrobiopterin cofactor Fig. 1 Major routes of tyramine

metabolism

in brain, kidney and gut.

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Thus, this test is considered to be a ‘trait marker’ for unipolar depression. Hale et al (13) have shown that possession of this trait is a favourable indicator for a response to tricyclic antidepressants, so the test does seem to be a marker for a fundamental dysfunction-an ‘inherited disorder of metabolism’. It will be argued here that the tyramine test has a firm theoretical basis, and that it ought to be used in the routine workup of depression, and that it could be a usefiul screening test in general practice. Phenolsulphotransferases (PSTs) are widespread in the body, and are commonly found in gut bacteria. In human brain, PST has a relatively high affinity for dopamine and noradrenaline, so the sulphoconjugation pathway of catecholamine breakdown is more important than previously realised (19). PSTs are not simply catabolic enzymes, but have a wide variety of control functions. such as the activation of cholecystokinin and other small peptides (20). Sulphation by PST requires a sulphate donor (PAPS), and when in relative excess, substrate is inhibited, because of its ordered bi-bi kinetics (21). Ultimately, though, PST control appears to be mediated at the level of transcription (22), so brain PST activity may reflect brain catecholamine activity. In granulocytes and platelets, PST is thought to reflect brain PST kinetics. and there are two forms: the M-form, specific for tyramine and dopamine, and the P-form, specific for other phenolic compounds. Bonham Carter (9) predicted that low tyramine excreters might have an inherited disorder of PST activity, but she failed to demonstrate such an effect (23). She also argued for a deficiency of the sulphate donor PAPS, but that was also excluded by the administration of oral cysteine supplements to patients (9). In 1990, Davis and Boulton used deuterium-labelled p-tyramine and improved assay techniques for platelet PST (24). They found platelet activities (particularly of the P-form) werereduced in their depressed group, but they offered no explanation for this effect. They also differed from Sandler et al by concluding that the tyramine excretion results did not differ from their controls, but on closer inspection, their excretion values were in fact concordant with those from earlier studies, however, their control group was at variance with earlier work. Thus it is true that all studies since 1975 have had comparable excretion values for depressed patients in respect of which Sandier chose the value 4.1 mg/3 h as the cut-off for the depression trait-marker (2). Positron emission tomography studies have demonstrated that major depressive disorders are characterised by a hypometabolism of the frontal cortex, some right/left asymmetry and a generalised com-

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promise of the basal ganglia (25-28). Frontal hypometabohsm also seems to underlie the depressions associated with epilepsy, Parkinson’s disease and primary affective disorder, and it has been suggested that similar metabolic disturbances underlie all these conditions (29). Xenon flow studies (30) demonstrate a decreased flow in the left hemisphere compared with the right in many depressives. EEG studies have confirmed this right/left asymmetry in a group of depressed patients when compared with normals or with schizophrenics (3 1, 32). In a mixed unipolar/bipolar population treated with tricyclic antidepressants, the right/left asymmetry present on PET scans before treatment resolved after successful therapy (27). Hypofrontality, however, which was also present prior to treatment, persisted after therapy, thus implying this abnormality might be a trait-marker of sorts for depression; of course, it probably also has a neurotoxic component in the frontal cortex and/or the basal ganglia. Baxter et al (25) argued that their unipolar depressed group could be distinguished from the bipolar and normal groups by a markedly lower ratio of head of caudate (metabolic rate) divided by that of the hemisphere; further, they demonstrated that this ratio increased following recovery. Thus they argued that the unipolar depressed patients suffered from an underlying ‘hypodopaminergic state’ with regard to innervation of the caudate nucleus. Evidence suggests that subcortical structures (such as the caudate and putamen) are functionally and anatomically related to the prefrontal cortex (33, 34). The caudate is specifically linked to the frontal association cortex (35, 36) and primate studies have shown that the caudate responds to visual stimuli that are behaviourally significant, that is, in a conditionalmanner. The caudate also mediates movement, and has some cells which respond unconditionally to sensory stimuli (37). Using magnetic resonance imaging (MRI), it has recently been demonstrated that depressed patients actually have smaller caudate volumes than controls (38). and that these volumes increase with age; indeed, there are structural changes in many elderly depressed patients (39). Perhaps this diminished volume in the caudate relay and integration centre might be considered one component of a ‘trait marker’ for depression. The caudate and the prefrontal cortex may become further compromised by a cumulative neurotoxicity. Figure 2 details some of the mechanisms of mitochondrial compromise: for instance, an interference with Na(+)/K(+) ATPase will depolarise cell membranes, permitting an intracellular accumulation of sodium; this can then relieve the voltage-dependent

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MEDICAL HYPOTHESES

INSULIN 3 GLUCOSE

t*Illl :a2+

I I +Z%DH

/TZJf

6. Ca+ Pump

IMg2+

I

SERUM MgZ+

Y

5. Na/H+ Pump

assumed to form a ‘functional unit’. Lithium Fig. 2 A composite cell. representing the neurone, the astrocyte and the oligodendrocyte: acts at 1, 5 and 7. Carbamazepine and valproate act at 4 and 6. Insulin has a rapid (in minutes) feed-forward effect on PDH in the mitochondria.

Mg2+ block on the NMDA (glutamate) channels and to a rapid influx of calcium, causing damage to intracelhtlar components (40, 41). Excitotoxic amino acids may also be released locally, both from neurones and from astrocytic glial cells (42). This regionalised neurotoxicity (with each episode of depression) may contribute to ‘hypofrontality’ and increasing caudate damage with age. The caudate receives discrete projections from dopamine-containing cell-bodies in the mid-brain (43, 44), and it has among the highest concentrations of dopamine in the brain, and also the highest concentration of tyramine (45, 46). Polyamines (like sper-

midine) and monamines (like tyramine) can modulate both the NMDA channel and mitochondrial pyruvate dehydrogenase (47, 48). In both Alzheimer’s disease and Friedrich’s ataxia, an abnormality of mitochondrial PDH (pyruvate dehydrogenase) has been noted (49), and it is one of the causes of the neurotoxicity observed in these conditions. Since regional blood flow is normally tightly coupled to metabolic activity in the brain, it is conceivable that anything which reduces energy production might result in neurotoxicity (41). This may lead to reduced blood-flow in regions like the caudate with a consequent loss of volume and function. With treatment, some function would be

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rest.ored, but the underlying deficit, the ‘trait marker’ would remain and the neurotoxic damage would be additive and cumulative with time. In terms of relative abundance, dopamine comprises almost half of all the catecholamine content of the CNS, although it has been cited less often that other amine transmitters in mood-disorder, it has been widely implicated in the pathogenesis of affective syndromes (50). The dopamine hypothesis of depression simply states that depression is associated with reduced levels of dopamine. This decreased functional activity seems to be related to the modulaltory properties of the ‘trace amines’-tyramine, octlopamine, and phenylethylamine (PEA). Boulton (46) has proposed that trace amines have a ‘synaptic activation’ or ‘amplifier’ function with respect to dopaminergic and noradrenergic neurotransmission. The trace amines, and particularly PEA, are structurally very similar to d-amphetamine. PEA is produced in many tissues, and peripherally, a large proportion appears to be rapidly biotransformed to ptyramine. Octopamine is mainly formed from PEA peripherally, and is excreted in milligram amounts (17). In the CNS, octopamine is formed rapidly from tyramine (51), and appears to have evolved as a more primitive form of noradrenaline, and is localised with it; it is a neurotransmitter in some lower species (52, 53). More recent work on caudate and cortical neurones has confirmed that p-tyramine, m-tyramine and PEA strongly potentiate the transmitter effects of dopamine and noradrenaline (54). The mechanism of this potentiation is not understood, but re-uptake inhibition does not appear to be a factor (55). Tyramine, when added to the striatum of anaesthetised rats, releases dopamine in a dose-dependent fashion, and this release is carrier-linked (56). It may also possess some measure of re-uptake inhibition, separate from the potentiation described for synapses (57). Polyamines and tyramine can modulate the levels of secondmessengers via G-protein coupled receptors (58), and Linnoila (59) has suggested that tyramine may regulate noradrenaline turnover, because he found that 24-h excretion of noradrenaline was related to urinary free tyramine output. In brain, octopamine is formed mainly from tyramine, and it can be released from synaptosomes by noradrenaline and electrical stimulation (60). Sandler et al have shown that octopamine, tyramine and phenylethylamine excretion are decreased in depression (61), but made no suggestion as to mechanism, other than to invoke a vague notion of a ‘membrane transport deficit’. In the older literature, it has been observed that the excretion of tyramine itself in urine was decreased

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in patients with Parkinson’s disease and schizophrenia and in children with attention-deficit disorders (62-64). This is interesting, given the relatively constant output of tyramine in urine from day to day. The urinary excretion of p-tyramine in any individual and indeed, between ‘normal’ individuals, is relatively constant, while the excretion of m-tyramine is remarkably so (65-67); both appear to be synthesised endogenously, and are unaffected by diet. Although p-tyramine is present in high concentrations in urine (greater, in fact, than the catecholamines or serotonin), its source and significance remain unresolved. However, it is clear that the kidney serves as the major site for the production of urinary dopamine and serotonin by the decarboxylation of plasma-derived precursors, DOPA and 5-HT (68). This decarboxylation is catalysed by aromatic-L-amino-acid decarboxylase (AADC. EC 4. I. 1.28), which is also capable of synthesising p-tyramine from plasma p-tyrosine (69). Although Boulton argues that a large proportion of tyramine is formed from phenylethylamine (PEA) peripherally, other argue that the decarboxylation of p-tyrosine is a major pathway for the formation of ptyramine in mammalian tissues (70). Figure 1 outlines both pathways. Brier et al have recently demonstrated that the (rat) kidney is an important site for the formation of urinary p-tyramine in vivo (71). Van Huysse (72, 73) has further supported the notion of renal production of p-tyramine by reporting that urinary excretion of the substance in the rabbit far exceeded its plasma delivery to the kidney. Since the renal sympathetic (efferent) nerves have been shown to exert a direct effect on rates of tubular reabsorption and excretion via dopaminergic and noradrenergic mechanisms (74, 75) the role of tyramine may also be as some sort of ‘synaptic activator’ there. In the midbrain and hypothalamus, when descending autonomic pathways were stimulated, there was a renal vasodilatation and potent natriuretic action due to the activation of intrarenal dopaminergic vasomotor fibres (76). The same enzyme (AADC) is important in neuronal tissues for the synthesis of catecholamines, serotonin and the trace amines (77). It seems that the physiological substrates of AADC are primarily LDOPA and 5-HT, since the Km for these substrates are the lowest (71). Sandler et al do not seem to have considered. the AADC system; it is present extraneuronally in high concentrations in kidney, liver and intestine (78, 69). The nonneuronal role of AADC has not been defined; however, a single gene codes for both the nonneuronal and neuronal forms of the enzyme (which are identical). It is a primitive enzyme, and the bovine form is 57% homologous with fruitfly enzyme, and some 37% overlap occurs with

396 a plant form (Cuthalareus): there is a cofactor site for pyridoxal, which is also highly conserved (79). AADC is coded for on chromosome 7, and it overlaps with the structure of other catecholamine biosynthetic enzymes (80). In the kidney, increasing concentrations of ptyramine and, theoretically its metabolites, do not affect the decarboxylation rate of p-tyrosine. AADC operates well below its saturation-point over the entire physiological range of substrate. However, plasma delivery of DOPA has previously been postulated to be a limiting step in the formation of urinary tyramine (81). This notion is further supported by the dramatic increases in urinary concentrations of p-tyramine seen in patients who have elevated levels of plasma tyrosine due to hereditary defects in tyrosine catabolism (the ‘tyrosiemias’ (71)). Finally, in the rabbit, a highly specific and reversible inhibitor of AADC, alphafluoromethyIDOPA, produces a significant decrease in the urinary output of p-tyramine (82). Using oligonucleotide probes derived from rat kidney AADC cDNA, AADC m-RNA was found in areas of the brain containing dopaminergic and serotoninergic cell bodies (77). It is conceivable, even attractive, to suppose that some defect in this enzyme might result in the ‘hypodopaminergic caudate’ proposed by Baxter, and that this defect could be reflected in peripheral sulphoconjugation. However, this enzyme seems an ancient one phylogenetically with little genetic diversity, and pyridoxal phosphate is abundant in the diet, so it is unlikely that the enzyme might be downregulated by any deficiency of cofactor. Turning to pharmacology, several studies have reported that at least half of depressed patients show temporary improvement following intravenous methylamphetamine or methylphenidate (83-85), and the relatively selective dopamine receptor agonist, piribedil, showed mild to moderate antidepressant effects in 12 of 16 patients, with greater improvement in those patients with lower excretion of the dopamine metabolite homovanillic acid (HVA) in the CSF (86). An antidepressant effect of the dopamine agonist bromocriptine (which is used to suppress the prolactin on lactation), has also been demonstrated (87, 88). Neuroendocrine studies have assumed that the changes in the tubuloinfundibular dopamine pathways may reflect changes in the mesolimbic and mesocortical systems, and dopamine is known to inhibit prolactin release, and to stimulate the release of growth hormone (50); both octopamine and PEA (‘trace amines’) have been shown recently to inhibit prolactin secretion (89).

MEDICALHYPOTHESES

It would appear that the trace amines play some role in the metabolic regulation of the catecholamines, particularly in the caudate nucleus. Perhaps in the depressed state, the caudate becomes ‘ischaemic’ and loses a proportion of its full volume and activity; it is almost certainly ‘hypodopaminergic’. In this way, areas of the frontal cortex would be downregulated, and limited neurotoxic changes might also supervene, both in the caudate and prefrontal cortical areas. (Tyramine is a powerful vasoconstrictor, and in depression, turnover is reduced, but local concentrations may actually rise). In the neurone, dopamine production from tyrosine occurs in the cytosol, and noradrenaline is formed from dopamine in vesicles. The monoamine oxidases are localised in mitochondria; they ‘scavenge’ residual catecholamines, ensuring a deficit within the neurone compared with the synaptic cleft, a necessary prerequisite for re-uptake regulation. To more fully explain the PET scan results for depression, it is necessary to consider both glucose transport and (mitochondrial) respiration of both neurones and astrocytes. This activity can be modulated by neuronal activity (and hence, by catecholamine turnover); since the rate-limiting enzyme for this turnover is tyrosine hydroxylase, the PET scans pick up a reduction in this activity as diminished respiration in dopamine-dependent regions. Similarly, since the astrocytes are insulin-responsive, impairment of the insulin receptor or its second messengers would also be reflected in reduced respiration on PET scan. Finally, since blood brain barrier (BBB) activity is modulated by both neuronal and astrocytic activity, the transport of tyrosine and other substrates (and of glucose and water) might be reduced in depression. Figure 3 illustrates this three-way interaction. Glucose transport and the insulin receptor will now be considered in more detail. The five recentlycharacterised glucose transporters provide a new level of understanding for the way glucose transport occurs across membranes, and the observation that they may also act as water-channels has implications with regard to pH and osmoregulation (90, 91). In the CNS, GLUT- 1 regulates flow across capillary endothelium and tight-junctions and both GLUT- 1 and GLUT-3 are active in astrocytic glial cells (92. 93). In spite of the fact that neuronal levels of m-RNA are much lower than that for astrocytes, glucose uptake is actually higher in neuronal cells (being tied to neurotransmission) than in astrocytes (94). An as-yet unidentified glucose transporter may exist for neurones (see Fig. 1). Glucose uptake in neuronal cells is not regulated by the same factors which alter expression of GLUT- 1

THE ‘CEREBRAL

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\

AGlucose)

391

\

,

/

Amino acids

BLOODBRAINBARRIER

-

Fig. 3 The ‘Functional Triad’ of neurone, astrocytic glial cell and blood-brain barrier: The p21 gene-product (if defective) would interfere witlh the tyrosine and tryptophan hydroxylases (by inhibiting BH4, tetrahydrobioptin). Similarly the insulin receptor phosphorylation would also be disturbed. This would result in an alteration of the blood-brain barrier activity and hence, depression.

in other cell-types. Factors like insulin, phorbol esters and insulin-like growth factors cause prominent ch#anges in GLIJT-1 m-RNA steady state levels, but fail to affect 2-deoxyglucose uptake in neurones (9598). This suggests that either post-transcriptional inhibition of GLUT-1 expression occurs in cells of neuronal origin, or that there is a different transporter responsible for the bulk of neuronal glucose uptake (94, 95). Pronounced changes in GLUT-l expression during rat brain development provide evidence for the presence of a glucose transporter whose activity would offset low GLUT-l levels (99, 100). In spite of GLUT- I being ‘insulin insensitive’, insulin and insulin growth-factor (IGF- 1) can effectively stimulate both GLUT-l m-RNA and 2-deoxyglucose uptake in astrocytic glial cells (96). From the evidence, it would seem that the neuronal glucose transporter system is relatively insensitive to various stimuli. On the other hand, an astrocytic glucose transport system capable of responding to many of the factors involved in glucose home-

ostasis may be the actual mediator of this (homeostatic) information between the peripheral circulation and specialised neuronal centres in the brain. (Astrocytes exert considerable control over the blood-brain barrier function, and they also invest some 95% of brain capillary endothelium with their foot-processes (lOl-103).) The notion of a three way functional neurone/astrocyte/endothelial modulatory unit has been presented in Figure 3. Overall, glucose uptake into the brain obeys a ‘facilitated diffusion’ kinetic (104, 105). Metabolism is generally tightly coupled to flow, although neurotoxic processes may over-ride this regionally. The close investment of cerebra1 microvessels with adrenergic and cholinergic filaments, as well as with mast-cells, means that local flow and metabolism may become uncoupled by immunologic processes or neural stimuli-for instance, in sympathectomised monkeys, stimulation of the VII nerve nucleus near the medulla oblongata resulted in flow changes in the parietal lobe. Similarly, in intact animals, stimulation of sympathetic nerves altered water

398 permeability of whole brain (106, 107). While GLUT1 may be modulated by plasma insulin and glucose concentrations the muscle/fat transporter (GLUT-4) behaves differently (108) and is the only transporter highly responsive to the binding of insulin; vesicles are recruited from within the plasma membrane, and are expressed on the surface of the cell in response to insulin binding. In rat brain, insulin is co-expressed with the much more widely distributed IGF-1, and they seem to overlap in receptor structure and activity (109, 110). Some of their biological effects include modulation of mitogenic activity, protein synthesis, neuronal maturation and oligodendrocyte myelin production (111, 112) and uptake of glucose into astrocytes: in addition, insulin and IGFs have been shown to share important neurotrophic properties with the nerve growth factors (NGFs), viz the capacity to enhance neuritic outgrowth (113). Insulin rceptors are widely distributed in rat brain (I 14, 115) and there may be regulation by insulin of neuronal connections between brainstem nuclei and forebrain regions: such modulation probably occurs via phosphotyrosine-containing peptides in these regions (116, 117). Brain insulin receptors also modulate peripheral glucose metabolism via several pathways (118) and centrally, insulin modulates monoamines (119). As previously demonstrated, the trace amines can potentiate the effects of dopamine or noradrenaline. In 1983, Sauter et al measured the effect of insulin on central catecholamines (120) and found that it caused a dose-dependent increase in noradrenaline and dopamine release. An in vivo study, employing ICV cannulation, demonstrated a similar effect, and that this release was increased in (alloxan) diabetic rats (121). Insulin receptors are disulphide-linked ohgotetramers composed of two heterodimers, each containing a 13OkDa alpha-subunit, and 90kDa beta subunit. Insulin binds to the extracellular alpha subunit, which stimulates autophosphorylation of the membrane-buried beta subunit, and thus, the expression of the tyrosine kinase activity. This beta subunit activation leads to activation of tyrosine kinase which is intrinsic to the cytoplasmic domains of the beta subunit. Activation of the tyrosine kinase represents an essential step in the transduction to the post-kinase level (122); possible mechanisms here include phosphorylation of substrate proteins (tyrosine residues and/or cytosolic serine kinases); an interaction with G-proteins, phospholipases or phosphatidylinositol kinases. The insulin receptor appears to possess an intrinsic accessory serine kinase, which may be regulated by glucagon via c-AMP (123). Insulin also modulates Na(+)/K(+)ATPase activity in

MEDICALHYPOTHESES

the cortex; depending on Mg2+ concentration, the enzyme could be either stimulated or inhibited (124). Streptozocin-induced diabetes in the rat accentuates regional differences in Na(+)/K(+) ATPase, decreasing its activity most in hippocampus and cortex. Thus, diabetes can modulate this major membrane pump (which is a component of the BBB), as can insulin itself (125). Indeed, in the diabetic state, Na(+) transport into the brain is decreased (126). The CNSperipheral interaction of insulin has become clearer in recent years; for instance, the allotransplantation of pancreas into cisterna magna was shown to control peripheral glucose utilisation, but insulin levels were double that of plasma (127); a three compartment model has been developed from work with dogs, and this model demonstrated that there could be a slow interchange between brain and the periphery involving the CSF compartment (128). The question of whether insulin is produced in the CNS remains unresolved, but IGF production is well-established (129, 130). Insulin and IGF-I and II are believed to have overlapping biologic functions (13 1). The IGF-I receptor is structurally similar to the insulin receptor, consisting of two extracellular alpha subunits and two transmembranous beta subunits (132). The IGF-II receptor consists of a single chain glycoprotein which binds mannose-6-phosphate, but not insulin ( 133, 134). IGFs are also known to influence acetylcholine transmission in the hippopocampus, as well as other regions in the rat (135, 136). A cleaved tripeptide derived from IGF-I has been shown to activate glutamate receptors, which may dramatically influence excitatory neurotransmission in this region (137). Thus, in addition to the probable neurotrophic actions of the peptide itself, subsequent processing of IGF-I may be an important aspect of IGF-I activity in the brain. Some studies suggest that the IGFs may play an important role in the modulation of excitatory transmission in the hippocampus, or may act as neurotrophic factors contributing to the maintenance of these neurones. The rat may provide a broadly accurate model for such activity in humans, because humans also exhibit large quantities of IGF receptors in the hippocampus (138). Insulin and IGFs can also exert neuroprotective actions; insulin at IOOO-fold higher concentrations probably acts at IGF-I receptor. Since neurotoxicity involves a loss of neuronal calcium homeostasis partly due to activation of NMDA receptors, the neuroprotection afforded by insulin and IGFs is most likely due to their ability to stabilise neuronal calcium homeostasis (139). Peripherally, the notion of ‘insulin resistance’ is focussing away from immunological processes at the insulin receptor (or from mutations affecting it), and is

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concentrating on defective phosphorylation, dephosphorylation or faulty activation of second messengers (140-142). Defects in any or all of these steps could compromise regional brain function, and diabetic rats demonstrate such defects. By analogy, such defects could be characterised by the paradigm of ‘cerebral diabetes’ but it must be appreciated that the primary defect may not be related directly to glucose uptake and disposition, but rather, would reflect an impairment of neuronal regulatory processes, and/or the modulation of astrocytes and of the blood-brain barrier. Pursuing the ‘cerebral diabetes’ paradigm, it has been1 found that mood changes may be associated with more subtle fluctuations in blood glucose than is usually understood for hypoglycemia (143, 144): hyperglycemia can reliably reproduce feelings of anger and sadness, for instance. Indeed, there does seem to b’e a loose association between (peripheral) diabetes and mood-disorder; while the incidence of diabetes in the general population is to the order of 2%, as is the incidence of affective disorder, yet the observed incidence of diabetes among patients with affective disorder, over a lo-year period (145), was 10%. The overall incidence for diabetes among other psychiatric patients was stili higher than expected at 3%, and this was after controlling for such factors as aige,weight and sex. Some older studies have report.ed a decrease in glucose utilisation in patients with depressive illnesses (146, 147) and a hyperinsulinaemia (148), effects which would tend to support an increased ‘insulin resistance’ associated with depression. There has also been one report of improved diabetic control following limited ECT (149), and ‘insulin coma therapy’ was used for some time with apparent success in affective illnesses (150), but less convincingly in schizophrenia ( I5 1). Further, lithium affects carbohydrate metabolism, and its long-term use may contribute to the development of diabetes and ‘insulin resistance’, probably by inhibiting the inositol pathway (152, 153). Once it is understood that there is a two-way interaction between the CNS and the periphery with regard to insulin, and that ‘insulin resistance’ at the level of the astrocytic glial cells may affect the function of the blood-brain barrier, then it is not difficult to understand how insulin resistance may affect mood. It seems also to be able to modulate monoamines and to affect cortical Na(+)/K(+) ATPase, various enzymes of respiration (like pyruvate dehydrogenase), mitogenesis and protein synthesis. The insulin growth factors overlap many of these functions, and add to the list. Egeland et al (154) reported that, among an Amish population, bipolar affective disorder was linked to

399 DNA markers on chromosome 11; other studies have not confirmed this (155, 156). It is of interest though, that on the short arm of chromosome 11, the genes for tyrosine hydroxylase, insulin, the IGFs and the h-ras oncogene are located. While affective disorder might not be linked with this locus via a single-gene mechanism, it is possible that there might be some sort of linkage to this locus for control processes common to the products of these loci. Several studies have also discounted a simple inheritance of diabetes in terms of the insulin receptor or tyrosine kinase (157, 158). However, there may still be a common defective control system between the insulin receptor and tyrosine hydroxylase activation. This defect might, for instance, be at the level of the phosphorylation processes necessary for their respective activations, (i.e. tyrosine/serine kinases). As discussed previously, a possible defect of AADC is a first-approximation explanation for the tyramine test (and Bonham Carter and Boulton wanted to invoke a defect of PST function (9, 24)). However, tyrosine hydroxylase would seem a more likely candidate. First, it is the rate-limiting enzyme for catecholamine synthesis. Second, it is a tetramer, with four genetic isoforms in primates (159), and it requires tetrahydrobiopterin (BH4) for activation and maximal function (and probably folate as well). The enzyme is phosphorylated at four serine sites for maximal activation, with the c-AMP phosphorylation at site 40 being the most important (160). It also appears that the genetic transcription of tyrosine hydroxylase is itself regulated by phosphorylatlon (161). In intact cells, insulin receptors can also become phosphorylated on serine or threonine residues. This is not due to the kinase activity of the receptor itself, but shows that the receptor can act as a substrate for other cellular kinases. These phosphorylation reactions seem to exert a negative control over the functional activity of the receptor, since they inhibit insulin-stimulated tyrosine kinase activity; indeed, glucagon seems to exert its effect via c-AMP linked phosphorylation of serine associated with the insulin receptor (123, 162). The insulin receptor contains three tyrosine residues, and is activated by phosphorylation on tyrosine kinase. Such phosphorylations are very rare in cells, as the majority of cellular protein kinases show a preference for either serine or threonine residues. The activity of both tyrosine hydroxylase and the insulin receptor are both regulated by phosphatases as well (163-165). In addition to activating its own signal transduction pathway, insulin can impinge on other messenger systems: thus, it may exert direct inhibitory control over adenylate cyclase and it may control G-proteins and their genetic regu-

400 lation, as well as phospholipase C and protein kinase A (166). Tyrosine hydroxylase (TH) is a substrate for a cAMP dependent protein kinase, as well as for other protein kinases. Inositol phosphates appear to play an important role in the activation and phosphorylation of TH; these effects may increase calcium-calmodulin dependent protein kinase activity, and possibly, calciumlphospholipid dependent PKC (167). Thus, insulin receptors and tyrosine hydroxylase are both tetramers which are activated by, and which act via phosphorylation of tyrosine and/or serine residues. They both interface with major second-messenger systems like c-AMP and phospholipase C, and with G-proteins (and the cofactor of TH, BH4 actually derives from GTP). It is intriguing to speculate that there might be a common control-point between insulin receptors and tyrosine hydroxylase, and indeed, several tyrosine-dependent serine kinases have been characterized (168). Neurotoxicity has been discussed in the context of reduced energy production, with release of the Mg2+ block in the NMDA receptor and consequent intracellular damage due to Ca2+ influx, along with release of excitotoxic amino acids (169), which may result in calcification. 2 patients with BH4 deficiency due to dihydrobiopterin reductase deficiency, had CT scans which demonstrated severe cortical and subcortical atrophy and basal ganglia calcification (170), and this picture was similar to that following methotrexate use (which inhibits cerebral tyrosine and tryptophan hydroxylases, because it inhibits dihydropteridine reductase (171)). It is also relevant that streptozocininduced diabetes in rats results in reduced BH4 levels and reduced activity of the same enzyme, dihydropterin reductase (172). Thus, diabetes might be considered the progenitor of some aspects of neurotoxicity, since it rest&s in impaired astrocyte and BBB function. A component of the insulin resistance described in diabetes has been attributed partly to impaired autophosphorylation of the insulin receptor. It has been suggested that the phosphorylation of serine and/or threonine residues of the receptor may reduce tyrosine autophosphorylation in diabetic rats, and in some cases, the ‘insulin resistance’ appears to have been related to the overphospohorylation of insulin receptors, because it can be partly relieved by phosphatases (173, 174). As there may be several levels of ‘insulin resistance’, so too may tyrosine hydroxylase be impaired, either at phosphorylation steps or at the level of BH4; some cases of autism, for instance, have been improved with BH4 supplements, and juvenile Parkinsonism (which is linked with the tyrosine

MEDICALHYPOTHESES

hydroxylase on chromosome 11) has similarly been improved (175). From neurotoxicity studies, it has been found that insulin and IGFs can modulate damage, particularly in the cortex, the thalamus and the basal ganglia (176). This raises the question of whether the insulin receptor interfaces with the E2-subtype of the NMDA receptor, which is found exclusively in forebrain. There are three NMDA receptor subtypes, and the functional properties of the channels are critically determined by the constituting E-subunit. The E2 subunit is expressed in the forebrain, and plays an important role in synaptic plasticity. Further, the El and the E2 channels can be modulated by protein kinases via G-protein coupled receptors (177). The NMDA channel appears to mediate hypoxic, hypoglycemic. epileptic and toxin-related damage (169, 178). This (glutamate) NMDA channel is also implicated in various degenerative changes in the CNS, and it probably also mediates intracerebral calcification. From the PET and CT scan data for unipolar depression, there is not only a functional impairment, but a structural one as well, and it may be this structural impairment in the caudate (secondary to energy impairment and neurotoxicity) which predisposes to functional disease in susceptible individuals. Basal-ganglia damage is age-dependent, and caudate damage does seem to be particularly prominent among elderly depressives. Conclusion It has been argued by Sandler et al (2) that the excretion of p-tyramine-o-sulphate in urine (following an oral load to tyramine hydrochloride) is a trait-marker for unipolar depression; PET scans associated unipolar depression with hypofrontality and reduced basal ganglia activity (25, 26) and MRI imaging demonstrates a reduced caudate volume (38). The trace amines (tyramine, octopamine and phenylethylamine) are ‘synaptic activators’ which potentiate the actions of dopamine and noradrenaline, probably also by interfering with some re-uptake and tyramine excretion may be a reflection of catecholamine turnover in the CNS (46). From Figure 1, it will be seen how the tyramine test and brain tyramine levels interface, viz via phenolsulphotransferase, as has been suggested by both Boulton and Bonham Carter (24, 9). Bonham Carter proposed that impaired platelet PST activity would be sufficient to explain the basis of the test, but she failed to demonstrate this (23); Boulton et al did demonstrate reduced platelet PST activity in unipolar depressives, and that this did not improve following treatment. Thus, Sandler’s original ‘tyra-

THE ‘CEREBRAL DIABETES’ PARADIGM FOR UNIPOLAR DEPRESSION

mine test’ probably reflects brain PST activity, because platelet PST reflects brain PST activity. PST requires a sulphate donor (PAPS) which is an adenosine moiety and which can regulate the enzyme in relation to its substrate. PST enzymes may reflect general brain energy turnover, and catecholamine turnover, and they are regulated at the level of transcription. Thus, the ‘tyramine test’ is primarily a reflection of gastrointestinal uptake of the tyramine hydrochloride challenge, and subsequent catabolism by MAO in the gut and PST in platelets (which possess some 77% of PST activity in plasma); and granulocytes which express some 19% (179). Unlike urinary tyramine, daily sulphate output fluctuates, due to dietary variatilon and contributions from gut bacteria, and this he.lps explain the high rate of false-negatives from thle test (II). Boulton has suggested PST-P as a reliable trait-marker for unipolar depression, and it can be: seen that this index might be made more accurate by also considering granulocyte PST-P. In the kidney, plasma tyrosine determines urinary tyramine production, and this is relatively constant for any individual. Tyrosine is derived from the diet, and in the liver, from the conversion of phenylalamine (Phe) (via phenylalamine hydroxylase (PH) and BH4). It is actively transported across the BBB, and across neuronal membranes; tyrosine and its BH4 cofactor is the rate-limiting enzyme of catcholamine synthesis, to DOPA, dopamine and nora,drenaline. Brain tyramine may be formed from tyrosine (via AADC. the same enzyme as in kidney), from phenylethylamine (PEA) (via PH) and from dopamine catabolism. Tyrosine hydroxylase is a four-subunit enzyme and four isoforms exist, but brain primarily has TH-1 and TH-2; it needs to be phosphorylated on four serine residues for maximal activity, and the c-AMP dlependent phosphorylation on Ser40 is the most subslantial. It is not difficult to conceptualise depression as an impairment of TH on two levels; first, protein kinases shared with the insulin receptor may be impaired. Second, BH4 may be impaired, and this would affect tyrosine hydroxylase, tryptophan hydroxylase and phenylalanine hydroxylase. With reduced catecholamine turnover, the trace amines would also be reduced, and so their ‘synaptic activation’ potentiation would be attenuated, particularly in the caudate. With reduced neurotransmission, the BBB would be attenuated in its activity. Indeed, Sandler et al did find a decreased excretion of p-tyramine and octopamine rnetabolites in depression, and ECT probably SUCceeds because of its cumulative effect on BBB permeability, on TH and BH4 activity, and secondarily, on dopamine levels (180, 181).

401

Insulin and the IGFs are important neuromodulators, and they may regulate neuronal glucose uptake indirectly by modulating glucose uptake in astrocytes. Astrocytes, neurones and the BBB form a three-way ‘functional unit’. Both insulin and tyrosine hydroxylase are activated by protein kinases (as are some NMDA subtypes). Overactivation of protein kinases has been suggested as a major factor in the neuronal damage which occurs in a number of neurodegenerative conditions (110). The cofactor BH4 is a complex pterin derived from GTP (the basis of all G-proteins), whose metabolism also relates to that of folate; it allosterically regulates its own activity (182) and that of TH, tryptophan hydroxylase (TPH) and PH. It can thus affect the turnover of both catecholamines and serotonin. There are several disease states where BH4 (or precursor) supplements have improved outcomes: in some cases of autism, juvenile Parkinsonism and phenylalanemia. It has been suggested that adult Parkinsonism may benefit from these agents in the near future (183), and it is noteworthy that, in the past, Sandler and Boulton have both suggested that supplements of phenylalanine or PEA might prove to be of therapeutic value in depression. Recently, TH has been shown to be inhibited by a heterocyclic amine derived from food (184). Heterocyclic amines are potent mutagens in Salmonella test-systems and are carcinogenic in animal models (18.5); they are derived from the frying and broiling of all meats, from food-additives (the azo food-dyes) and are also found in soft-drinks and hard candies. They are most commonly found in cigarette smoke and petroleum fumes (186-188). They can also be uptaken into dopaminergic nerve terminals ( 189) and they are differentially metabolised by ‘fast’ acetylators (these individuals have an increased exposure risk) (190). These substances can inhibit AADC, and both tyrosine and tryptophan hydroxylase reversibly, but the BH4 cofactor is inhibited noncompetitively (191, 192). This model implies that oral supplements of BH4 and SHTP together may be beneficial in the treatment of these conditions. Heterocyclic amines have been implicated as factors which may impair neurotransmission. Magnesium deficiency may be another factor (193). It has been argued that the intake of Mg has been falling since the turn of the century (194) and several large studies have demonstrated apparently inadequate intakes (195, 196). Reduced cytosol magnesium can impair the membrane pumps (197) and can relieve the NMDA Mg2+ block, thus facilitating neurotoxic damage. It is of further interest that fluoride not only impairs the Na(+)/K(+) ATPase, but also the absorp-

402 tion of magnesium (198). Vanadium, which scavenges fluoride and other halides within cells, seems to assist the insulin receptor transduction steps independent of the phosphorylation step, possibly by facilitating protein kinase activity and this may also have therapeutic benefit (199, 200). While a single-gene linkage has been excluded at the 11~15 locus for bipolar disorder, a defect in a system jointly affecting the phosphorylation of the tyrosine hydroxylase and the insulin receptor: and a tyrosinelserine kinase would be a good candidate. Phospholipase C has already been proposed as another possibility (201). A major cause of ‘insulin resistance’ has been related to defective phosphorylation/phosphatase reactions in the cell membrane. If a common protein kinase defect were considered to be the basis for the ‘trait markers’, then hypofrontality. impaired caudate and reduced catecholamine turnover (as indirectly reflected in the tyramine test) would also be explained. If the pterin cofactor BH4 were additionally impaired, then this would ‘tip the balance’ for many individuals. Indeed, in depression, BH4 levels are abnormal (202, 203); in addition. impaired energy production due to this protein kinase dysregulation could lead to variable neurotoxicity. Finally, since MAO activity increases with age, possibly due to less effective inhibition (50, 204), middle-age onset of many depressions, and geriatric depression in particular, would be explained. It is proposed, then, that unipolar depression is a cluster of disorders: an underlying inherited protein kinase defect, the ‘trait marker’ would be overlain by neurotoxic processes and diet-related or environmental toxins (which impair TH, TPH and PH). Secondary effects on the BBB perpetuate the insult (via the astocyte-endothelial cell unit); Sandier et al proposed a ‘generalised membrane defect’ in depression, and this can be explained by the ‘functional triad’ model. ECT not only stimulates BBB permeability and function, it also stimulates TH and BH4 activity and then dopamine turnover. Thus the ‘hypodopaminergic caudate’ and hypofrontality are amplified by neurotoxic damage. Therapeutically, depression might usefully be treated with oral supplements of BH4, magnesium and vanadate. Regular infusions of IGF-1 (which has recently been used to overcome severe peripheral insulin resistance (205, 206)) might stimulate the BBB and neuronal activity, and there is the possibility that damage associated with de-myelination might be repaired in part. In summary, the ‘tyramine test’ is simple and cheap and is suitable for use in general practice; it could probably be improved by measuring platelet and granulocyte PST-P directly. In one sense, unipolar depres-

MEDICAL

HYPOTHESES

sion can be viewed as ‘cerebral diabetes’ which is a useful notion in terms of reducing public anxiety regarding mental illness. Such reconceptualization may also have important forensic implications as well. Thus, when unipolar depression is reconceived as ‘cerebral diabetes’ it carries the opportunity for major attitudinal change both scientifically and socially. It is based on the model of neurone/astrocyte/BBB as a unit; it proposes that a common protein kinase is genetically impaired and which therefore impairs the insulin receptor and tyrosine hydroxylase activities. The h-ras-oncogen would be one candidate, since one of its products, p2 1 ras, can modulate protein kinases, and p21 ras is an intermediate of the insulin and growth factor signal transduction pathway involved in the regulation of gene expression and mitogenicity (207, 208). It is of great interest that a Yale group (209) has recently demonstrated that the dopamine D4 receptor is localised near the h-ras-oncogene on chromosome 1 lp 15. The cofactor of TH, PH and TPH can be impaired by food additives, cigarette and petrol fumes and other environmental toxins, and this may add to genetic impairment. Cumulative impairment leads to neurotoxic damage, worsened by magnesium deficiency. Natural therapies for unipolar depression are suggested, and these include oral BH4 supplements, magnesium/vanadium supplements, and regular IGF-1 infusions (possibly in lieu of ECT). The ‘cerebral diabetes paradigm’ is therefore presented as a cogent model which explains a large number of observations related to unipolar depression and which makes verifiable predictions about genetic, environmental, and therapeutic issues. Acknowledgements We wish to extend our gratitude to Magda Heaslip for her excellent preparation of the computer generated diagrams.

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