Studies of Neurotransmitter Function

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Neurotransmitter function in bipolar and nonbipolar depressions has been investigated using transmitter metabolite levels in body fluids, receptors on peripheral cells, and receptor function using agonist or neuroendocrine challenge techniques. The studies were guided by a series of simple and heuristically useful hypotheses, summarized in Table 2-1. Despite supporting data for each hypothesis, each also had contradictory findings. At a fairly early stage, it was possible to reject hypotheses that major depression, bipolar or otherwise, stemmed from too much or too little of any transmitter (Maas et al. 1991). The second generation of hypotheses held that balances between transmitters, such as norepi-nephrine versus serotonin (Prange et al. 1974) or norepinephrine (NE) versus acetylcholine (Janowsky et al. 1972), were abnormal. The third generation of hypotheses, logically very close to the first generation, held that second messenger function associated with transmitter receptors was abnormal, usually with increased activity in mania (Lachman and Papolos 1995; Stewart et al. 2001).

Most neurotransmitter studies have focused on norepinephrine. There is a state-dependent elevation of NE function in manic and mixed states (Swann et al. 1987), but there are no reliable changes in NE or its metabolite levels during depression (Koslow et al. 1983). However, NE is apparently metabolized abnormally during depression, with lower relative concentrations of intracellular metabolites, interpreted as consistent with increased, pulsatile release of NE (Maas et al. 1987). This also occurs in mania (Swann et al. 1987). A discriminant analysis of NE and epinephrine metabolite excretion patterns resulted in the D-score, which is generally lowest in bipolar I depression, higher in bipolar II

TABLE 2-1. Classical transmitter hypotheses in bipolar disorder

Hypothesis

Supporting data

References

Norepinephrine high in mania, low in depression

Norepinephrine high in mania and low in depression superimposed on low serotonin in both High norepinephrine and low acetylcholine in mania; opposite in depression

Low GABA

Levels of metabolites in body fluids, responses to treatments, precipitation of episodes, animal models Levels of metabolites in body fluids, responses to L-tryptophan

Bunney et al. 1972

Prange et al. 1974

Effects of cholinomimetic Janowsky et al. 1972 drugs on affect, physiological sensitivity to cholinomimetic drugs GABA levels in body fluids, responses to treatments, animal models

Brambilla et al. 2003

depression, and highest in other depressions (Grossman and Potter 1999; Schatzberg et al. 1989). (The D-score is a mathematical calculation of different amine metabolite levels that "discriminate" between different types of depression [Schatzberg et al. 1989].) This interesting finding is hard to interpret physiologically. The proportion of NE that is metabolized intracellularly rather than excreted unchanged may be easier to interpret physiologically but is reduced in both unipolar and bipolar depressions (Maas et al. 1987).

Regardless of differences in amounts of NE and its metabolites, patients with bipolar disorder appear to have increased reactivity to NE. More so in bipolar than in unipolar depressions, noradrenergic function is more strongly related to mood and psychomotor impairment (Swann et al. 1999), treatment response (Maas et al. 1984), and relationship to stressful events (Swann et al. 1990). Subjects with bipolar disorder have increased sensitivity to subjective effects of stimulants (Anand et al. 2000). Pharmacologically increased NE precipitates mania in subjects with bipolar disorder (Price et al. 1984) and may selectively improve bipolar depression (Osman et al. 1989). Subjects with bipolar disorder have a greater noradrenergic response to orthostasis (Rudorfer et al. 1985) compared with those with unipolar disorder or to controls. A postmortem brain study showed that patients with bipolar disorder had more noradrenergic neurons in the locus coeruleus than did unipolar subjects or controls (Baumann and Bogerts 2001).

Studies of serotonergic function, generally assessed using neuroendocrine or other responses to antagonist, agonist, or precursor infusions, have generally been consistent with reduced functional capacity but have yielded little evidence for specificity between bipolar and unipolar disorders (Price et al. 1991; Sher et al. 2003; Sobczak et al. 2002). Low serotonergic function may be related to potential suicidality in a manner independent of affect or diagnosis (Goodwin and Post 1983; Mann 1999), or the relationship may be stronger in subjects with unipolar depression than in those with bipolar depression (Asberg 1997). Perhaps the most interesting evidence that there might be a specific relationship between serotonergic function and bipolar disorder is a study that compared relatives of bipolar disorder patients with controls, which found that tryptophan depletion lowered mood and increased impulsivity in relatives of patients with bipolar disorder (Quintin et al. 2001).

Other transmitter-related findings in bipolar depression include increased sensitivity to acetylcholine (Sitaram et al. 1982) and reduced Y-aminobutyric acid (GABA) in body fluids (Brambilla et al. 2003; Petty et al. 1993). Cerebrospinal fluid (CSF) GABA levels in euthymic subjects with bipolar disorder were the same as those in control subjects (Berret-tini et al. 1982, 1986); therefore, low GABA levels may be a characteristic of depressive episodes in general. There is also a complex array of endocrine findings, most involving the hypothalamic-pituitary-adreno-cortical axis (HPA). Reported HPA abnormalities include increased cortisol excretion with reduced sensitivity to negative feedback regulation, resulting in an increased incidence of dexamethasone nonsup-pression in both bipolar and nonbipolar depressions (Stokes et al. 1984). Despite original suggestions that HPA dysfunction was related to a specific type of treatment-responsive depressive episode, there are no reliable or specific clinical differences, other than increased anxiety, between major depressive episodes with and without HPA axis dysfunction (Kocsis et al. 1985). In bipolar disorder, CSF cortisol concentrations and degree of dexamethasone suppression test (DST) nonsuppression are related to depressed mood, especially in mixed states (Swann et al. 1992). In general, the complexity and varying specificity of these transmitter and endocrine findings suggest that they are secondary to some other underlying process.

Table 2-2 summarizes relationships between biological findings and specificity of bipolar depression relative to unipolar depression, and euthymic bipolar control condition. Most effects appear to be related to presence of depression rather than to diagnosis, but there are interesting exceptions. Changes in NE appear state-dependent, but sensitivity to NE appears abnormal regardless of state and differentiates bipolar from unipolar disorder. Most serotonergic abnormalities seem to be similar in bipolar and unipolar disorder, but blunted response to 5-hydroxytryptophan in euthymic subjects and abnormal behavioral responses to tryptophan depletion in relatives of patients with bipolar disorder imply that there may be trait-dependent abnormalities in serotonergic function with some degree of specificity to bipolar disorder. There is relatively little information about other transmitter systems, largely because they are more difficult to study neurochemically, lacking convenient stable metabolites or well-defined ligand infusion procedures.

More recent data suggest that pathophysiology might involve systems related to neuronal adaptations to changes in activity, or second-messenger systems that might underlie the apparent complexity of most biological data. The nitric oxide system is a strategic candidate (Akyol et al. 2004), with one indirect study showing lower plasma argi-nase and higher nitrite levels in subjects with bipolar disorder compared with control subjects (Van Calker and Belmaker 2000; Yanik et al. 2004). Cell signaling systems, particularly involving inositol and protein kinase C, may be involved in effects of so-called mood-stabilizing drugs (Harwood and Agam 2003). Systems involving membrane lipids, such as the arachidonic acid cascade, may be important and are potentially accessible to brain imaging studies (Rapoport 2001). Biological investigations in bipolar disorder are undergoing a transition from studies driven by pharmacological effects and descriptive data to studies aimed at physiological systems that may underlie depression or the susceptibility to its recurrence.

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