Depression and the drugs that treat it

Depression is defined by the Oxford Dictionary as “a state of low spirits or vitality”.

In this form, most of us have probably undergone it at some point, but for some
people feelings of low self esteem, guilt, low libido, misery, sleep disturbance, loss of
appetite and loss of motivation can last for weeks or months. This is the medical
condition of depression, and requires psychiatric help. It is quite a common problem,
one in which our therapeutic abilities are some way ahead of our mechanistic
understanding. There are two types of depression: unipolar and bipolar, and the two
seem to have different aetiologies, requiring different drug treatments. Bipolar
depression will be discussed later in the essay, since it requires different drug therapy
from unipolar depression, and seems due to a different aetiology. It is customary to
further subdivide unipolar depression into reactive depression (75%, precipitated by
stressful life events) and endogenous depression (25%, familial pattern and unrelated
to internal stress). Despite this, there seems to be little difference in the efficacy of
treatment between these two types of unipolar depression, and therefore this
distinction will be ignored for the purposes of this essay.

Antidepressants, or at least drugs that alter the mood, have been known about for a
very long time. Coca leaves have been chewed for hundreds of years. Amphetamines
have similar mood stimulating properties. These are both uptake 1 inhibitors. Opiates
also have mood elevating properties, probably exploiting the endogenous pathways of
enkephalins or endorphins. The antidepressant properties of alcohol have also been
appreciated for a very long time. These drugs, however, are not used as
antidepressants nowadays. The first modern antidepressants, the monoamine oxidase
inhibitors (MAOI’s) and the tricyclic antidepressants (TCA’s), were discovered in the
1950’s, although I am not sure that their full impact was appreciated at the time. The
first paper on imipramine, the first TCA, was presented to an audience of just 12!

In contrast to this early development of effective drug therapy, the mechanisms of

depression are poorly understood. Information is generally from four sources
(Leonard 2003). Autopsies of suicide victims (probably depressed people, but this is
not guaranteed) often reveal changes in biogenic amines. This information has to be
tempered, however, by the realisation that they will often have killed themselves with
a combination of alcohol and psychoactive drugs, so it is not always clear which
changes are due to the depression and which to the suicide. In any case, the large
delay between death and autopsy can affect the results. Second, the cerebrospinal
fluid of patients with depression can be analysed for changes in amine metabolites, as
can their urine. The problem here is that the exact concentrations can be affected by
many factors, such as diet, and can also be altered by treatment. Third, there often
seem to be accompanying endocrine disorders in these patients, which can shed some
light on the underlying mechanisms. Finally, platelets have a neuroectodermal
embryological derivation, and changes in their receptor function and density can
suggest the central nervous pathology. They can be viewed as easily accessible
examples of central neurons1. Similarly, abnormalities in receptor function of
lymphocytes can also point to problems. Responses can be compared in all cases
1
Although it is not so simple. They are not connected to the neural system, so any changes after birth
presumably wouldn’t affect them. Also, they may be affected secondarily to the alterations in various
plasma hormones seen in depression.
before and after effective treatment. One problem with these studies is that they are
difficult to perform, and necessarily small scale. It is also often difficult to replicate
the results, necessary for the reliability of experiments.

The most important mechanistic theory of depression is the monoamine theory, which
stems from Schildkraut, 1965. He proposed that depression was due to a deficit of
noradrenaline. Later, this hypothesis was extended to include serotonin. Since NA is
generally linked with drive and motivation, and 5HT with mood, this conveniently
accounts for both the behavioural and emotional effects of depression (and therapy).
The hypothesis was based on the mechanism of the antidepressant drugs, which all
seem to increase levels of serotonin, noradrenaline, or both. TCA’s block reuptake of
NA and 5HT. MAOI’s increase intracellular stores of NA and 5HT by inhibiting their
breakdown. Reserpine, on the other hand, which depletes the intracellular vesicles of
noradrenaline, seems to precipitate depression in patients in remission, as does α
methyl p tyrosine, which is a “false substrate” for the tyrosine hydroxylase enzyme,
and thus lowers synthesis of noradrenaline. This hypothesis can be extended to mania,
which is seen as resulting from an excess in these neurotransmitters. α methyl p
tyrosine seems to calm manic patients.

Evidence such as this can seem quite persuasive, but there are some problems. Rang
and Dale state that there are some drugs which have different effects from those
predicted by this theory, although they do not offer any specific examples. They claim
that cocaine and amphetamines do not have any antidepressant effects, although I am
not sure if this is totally true. Even if it were, might this not be caused by their side
effects (vasoconstriction and NA release respectively) masking their antidepressant
activities? Some antidepressants do not seem to affect the 5HT or NA axes.

Leaving this aside, if this hypothesis were the whole story one might expect
immediate changes from taking antidepressants. But they actually take 2-3 weeks to
have optimum effect. Pharmacokinetics is not enough to account for this, since it
takes only a week for the drugs to reach their final concentration in the brain2. Also,
there are some antidepressant drugs which do not have any effect on monoamine
transmission. It is recommended to take antidepressants for 12 to 18 months, even if
one’s mood changes before this, to ensure these long term effects, according to
prozac.com. Even leaving aside the experimental evidence for a moment, there are
some logical complaints which can be levelled against this theory3. Supplying a
transmitter precursor will only increase transmitter release if that is the rate limiting
step, and I am not sure whether this is the case for NA and 5HT. It also assumes that
the neurons themselves are intact (although they seem to be). Finally, it does not
suggest a relationship between the 5HT and NA: all that can be said is that it is
“poorly understood”, although adrenergic and serotonergic do affect each other, with
there being 5HT receptors on adrenergic neurons, and NA receptors on 5HT neurons.
The clinical evidence suggests that drugs acting on either of the two are equally
effective, but research has concentrated on serotonin re-uptake inhibitors, or at best a
combination of NA and 5HT uptake inhibition.

2
Imporvements seen before this with antidepressants are thought to stem from their sedative effect, and
perhaps some form of placebo effect. The 2-3 week delay is also seen with electroconvulsive therapy,
so must be quite important.
3
From Rang and Dale
There have been attempts to find experimental evidence for the amine theory, but
these have proved inconclusive. Referring to the menu of experimental approaches
above, the most direct approach is to measure the concentration of 5HT and NA
metabolites in the urine of depressed patients. The main metabolites are 5-HIAA and
MHPG, respectively. In bipolar patients, MHPG levels are markedly reduced during
depressive phases, and raised during manic phases, although in unipolar depressives
the results are not so clear. Rang and Dale point out that peripheral, and thus plasma,
NA and MHPG levels might be higher in depressed than normal patients, since they
demonstrate abnormal anxiety, which will have sympathetic effects. Evidence
concerning 5-HIAA levels in depressed patients, however, is even less conclusive,
although Leonard 2003 claims that there is a reduction in 5-HIAA in the CSF of
severely depressed patients. Rang and Dale suggest that the low 5-HIAA levels found
in suicide victims is possibly due to violent behaviour rather than to depression. One
interesting (but surely unethical?) recent experiment however, showed more of a role
for L tryptophan, the precursor of 5HT (Human Pharmacology, Molecular to Clinical
Brody et al.). When patients who were being treated on an SSRI are given an amino
acid drink that is deficient in L tryptophan, they have rapid (less than 24 hours) onset
of depressive symptoms. The other amino acids compete with the L tryptophan for the
amino acid transporters across the blood brain barrier, there is insufficient L
tryptophan to synthesize adequate levels of 5HT, 5HT levels fall and the patient
relapses into depression.

The brains of depressed patients who commit suicide show a number of interesting
changes. There is an increased density of β2 adrenoceptors in cortical regions, and on
their lymphocytes. This is what would happen if there were indeed a decrease in NA
levels (a type of denervation supersensitivity?!). Since levels of β adrenoceptors seem
to decrease following effective treatment, this is probably quite an important marker
for the depressed state. Other changes include increased density of 5-HT2A receptors in
limbic regions (by the same logic consistent with decrease in levels of 5HT), and on
platelets. There seems to be a defect in 5HT2A signalling, at least in the platelets, since
addition of 5HT to them causes decreased aggregation in vitro in depression. There is
increased muscarinic receptor density in limbic regions. If this reflects increased
activity of the muscarinic acetylcholinergic system, this could antagonise the
noradrenergic system, leading to reduction in its effects. This could contribute
towards an explanation of the amine theory. There has been also been suggestion of
dopamine involvement in some (particularly severe) types of depression: perhaps
there is a defect in reward pathways, due to a dopamine defect? Open label studies
have demonstrated possible antidepressant function for the dopamine agonist
roxindole, and the dopamine uptake inhibitor pramipexole (Leonard).

There are some intriguing neuroendocrine changes. Hypothalamic neurons receive

input from NA and 5HT systems, affecting their discharge (Rang and Dale). There is
increased release of CRH from hypothalamic nuclei (parvocellular cells of the
anterior hypothalamus). This seems to stem from a defect in the feedback: application
of dexamethasone, a steroid which would normally cause a fall in CRH due to
negative feedback, seems to have reduced effect in depressed patients. There are
glucocorticoid receptors in the nuclei of catecholamine and 5HT containing neurons
in the brain, and these seem to be subsensitive in depression. CRH is widely
distributed in the brain, and has behavioural effects that are both distinct from its
systemic effects, and which mimic depression. These effects include diminished
activity, loss of appetite, and increased signs of anxiety.

The link between neural and immune function has been the focus of much recent,
interesting research. Glucocorticoids inhibit many aspects of cellular immunity, and
so there is an immediate possible link between depression and impaired immunity.
There is evidence to suggest that there are raised levels of prostaglandins (PGE2) in
the plasma of untreated depressives, which are then normalised following successful
treatment (Leonard 2003). This will cause the microglia of the brain to produce
increased IL1β, IL6 and TNFα, which conceivably could have a role in reducing the
amine release in the brain4. The obvious experiment is to use a COX2 or COX3
antagonist to see if this has any effect on depression. While I am not sure if has been
done explicitly, it is worth noting that the tricyclic antidepressants have some use in
severe rheumatoid arthritis due to their COX2 inhibitory activity5.

Levels of growth hormone seem lowered in the chronically depressed, and this is the
most consistent effect on the hypothalamic-pituitary axis in chronic depression
(Leonard). Normally, clonidine, an α2 agonist, will cause release of growth hormone.
This response, however, is diminished in depressed patients. The loss of α2 response is
another pharmacological hallmark of depression, and again points towards a
functional loss of noradrenergic function in depression. Whether this is a particular
problem in depression is another question entirely, since it does not seem to change
after antidepressant treatment.

Thus the monoamine hypothesis is not at all clear cut. There could well be other
transmitters involved, such as acetylcholine alluded to above, and possibly even
dopamine. Even if the hypothesis is fundamentally correct, it still needs to be
modified in terms of the long term changes that occur in depression (even if one just
attributes these to chronic amine imbalance, it is important to recognise it).
Modifications to the amine hypothesis are important in explaining the actions of
antidepressant drugs, explaining why those with ostensibly similar mechanisms work
differently, and identifying new targets for therapy. More recently, a general idea of
“transmitter imbalance” has been proposed, but this seems quite vague.

One way of ascertaining what is wrong in depression is to look at the long term
effects of the antidepressant drugs. Psychological improvement can be correlated
against changes in receptor activity. There is normally a decrease in β2 activity, which
makes sense if one sees this as symptomatic of the loss of NA in depression, although
not, if like Rang and Dale, one views the original β2 supersensitivity as being at the
root of the problem (β2 antagonists have no antidepressant activity). There is a
continued deficit in response to clonidine. Therefore, this should be viewed either as a
trait marker for the condition (a genetic susceptibility to depression?), or as a useful
effect since there is a loss of presynaptic inhibition. 5HT2 receptors are also
downregulated, which again correlates with the idea of 5HT levels returning to
normal. There is also a decrease in cortical muscarinic receptor density (which
removes the antagonism of the cholinergic effects on the NA system)6.

4
The alternative hypothesis being that the depression somehow causes the raised prostaglandin levels.
5
Tricyclic antidepressants are often useful for treating chronic pain, for example that of trigeminal
neuralgia.
There are several categories of antidepressant drug. These broadly divide into
MAOI’s, drugs that inhibit monoamine reuptake of some sort, and miscellaneous
drugs. Reuptake of 5HT and NA occur by two different mechanisms, but the two
mechanisms are sufficiently similar to both be blocked by the same drugs in many
cases. The uptake mechanisms are the most important in terminating the action of
these amines. cDNA cloning techniques have recently demonstrated the structure of
the transporter proteins involved: NET’s (NA) and SERT’s (5HT). These are closely
related transporter proteins, and are also similar to the glycine, GABA and dopamine
transporters. They have twelve transmembrane domains, and rely on sodium
cotransport to provide the energy for reuptake. They have a 200fold specificity for
their particular amine, and are only expressed in neurons secreting that amine.
Amphetamine is a substrate for transport, and is in fact stored in the storage vesicles
upon its uptake into the cell, thus causing release of the amine that was originally in
the vesicles by reverse transport, and inhibiting its reuptake. Cocaine, and for that
matter the tricyclic antidepressants, bind to the transporter. In a sense I am surprised
that drugs acting on the NA and 5HT receptors are not utilised more, since they would
allow more selective effects, but there is some scope for their use as adjuncts for
treatment. This does however seem to be the direction in which the therapy is
developing (e.g. the second generation tetracyclic antidepressants, see below).

Inhibitors of monoamine uptake include the tricyclic antidepressants, such as

imipramine and amitriptyline, which inhibit uptake of both NA (uptake 1, the easily
saturable neuronal uptake) and 5HT, although much more effective for NA than 5HT.
They have no effect on the uptake of dopamine. In theory (as long as it is the amine
theory) they are wonderful, but they have enormous side effects7. This is linked to the
fact that they are antagonists at muscarinic receptors, H1 receptors, and α1
adrenoceptors. They also block the voltage gated sodium channels in the heart, at least
according to Leonard, although Rang and Dale state that they actually block HERG
potassium channels, and that the Q-T interval is prolonged. The most noticeable effect
of the H1 antagonism occurs centrally, and leads to sedation, which is probably quite
useful. The other side effects, however, are not so desirable. The α1 antagonism
causes postural hypotension due to inhibition of vasoconstriction. The muscarinic
antagonism causes the usual effects of atropine: dry mouth, tachycardia, dilated
pupils, blurred vision due to inhibition of accommodation and urinary retention8.
These will often cause non-compliance, which can be as high as 40%. In contrast, the
type I antidysrhythmic action can cause heart block and death- particularly with the
tachycardia due to the anti-muscarinic effect. The therapeutic index for TCA’s is
typically only between 5 and 10, so a relatively small overdose is sufficient to cause
death. Since we are discussing the treatment of depressed patients, of whom up to
15% will die by committing suicide, this is highly undesirable. In fact, 25% of the
suicidal 15% kill themselves with an overdose of TCA’s. TCA’s also potentiate the
effect of alcohol, possibly another particular danger for some depressed patients, and
deaths have occurred through severe respiratory failure after drinking. Despite these
6
Changes have also been described in many other receptors, including dopaminergic and GABAB
receptors. GABAB receptors enhance NA release in the cortex.
7
The only exception is lofepramine, which seems to lack these side effects for reasons as yet unknown.
It is therefore widely used. The relatively new SNRI’s, such as venlafaxine, seem to have similar basic
effects as the TCA’s, but do not have the same structure, and does do not have the same side effects or
cardiotoxicity. They are now being used more widely.
8
Lofepramine has been widely lauded for its lack of cholinergic effects. But given the possible
abnormalities of cholinergic transmission in depression, could this possibly diminish its effectiveness?
side effects, however, and having been superseded by newer drugs, the TCA’s remain
widely prescribed.

There are also selective serotonin reuptake inhibitors: the SSRI’s. These include
fluoxetine (Prozac), fluvoxamine, paroxetine and sertraline. Since these drugs affect
5HT and thus mood, they are in fact useful for all sorts of disorders, including
anorexia, bulimia, obsessive compulsive disorder, panic disorder as well as depression
(at least according to prozac.com). In addition to causing inhibition of reuptake, thus
changing 5HT levels, there is also the idea that they down regulate the inhibitory
5HT1B autoreceptors, which inhibit the release of 5HT. This increases the release the
release of 5HT still further. Giving the SSRI with the 5HT1B (another 5HT release
lowering receptor) antagonist pindolol and with a β blocker enhances its effects still
further. Prozac is currently the most prescribed antidepressant. They do not have
cardiotoxic effects, have little effect on NA reuptake, and do not inhibit the
connoisseur’s enjoyment of red wine and cheese (MAOI’s: see below). in vitro it is
clear that SSRI’s serve to inhibit reuptake of radiolabelled 3H 5HT, but in vivo it
takes at least two weeks for there to be an increased release of 5HT from neurones in
the frontal cortex, despite this immediate uptake inhibition. So the effects of this drug
are probably not as simple as superficial analysis might suggest.

Despite SSRI’s seemingly having fewer side effects than TCA’s, studies show that
there is relatively little difference in terms of patient acceptability (Song et al. 1993).
The exact nature of these side effects differs between the individual SSRI’s, and
therefore seems more to do with their effects on other receptors, than any inherent
side effect of their inhibition of 5HT reuptake. For example, both fluvoxamine and
sertraline are σ1 agonists, which could contribute to “serotonin syndrome”, where
SSRI’s and MAOI’s given together cause tremor, hyperthermia and cardiovascular
collapse. Citalopram has a slight antihistamine action, has a slight sedative effect. In
general, however, typical side effects are nausea, anorexia, insomnia, loss of libido,
and failure of orgasm. These are basically behavioural effects, which makes sense
when one considers the importance of 5HT in learning, memory, and many other
cortical functions. The drugs also inhibit platelet 5HT uptake, but I am not sure what
the physiological role of this is, and certainly have not seen any reported effects on
clotting.

The noradrenergic equivalent of the SSRI is the inhibitor of NA reuptake (NARI). An

example is reboxetine. It is as effective in reducing depression as the SSRI’s, but drug
companies do not seem overly interested in this line of research. Recent research
seems to take serotonin reuptake inhibition as a sine qua non in antidepressant
therapy, and there are no new NARI’s in development.

Selective 5HT and NA reuptake inhibitors, SNRI’s, are the products of this recent
research. An example is venlafaxine. Although their therapeutic effects are quite
similar to the TCA’s, they are structurally unrelated, and thus do not have the same
side effects. At low doses, it has a predominantly SSRI effect, but at higher doses also
inhibits NA uptake. One problem with introducing an NA aspect to what is otherwise
an SSRI is that there is the potential for hypertension, even at therapeutic doses.
Another problem is that venlafaxine is three times as likely as Prozac to cause death if
taken in overdose, possibly due to its adrenergic effects although I am not certain.
MAOI’s are the other major class of traditional antidepressants. These are irreversible
inhibiters of MAO. In particular, they inhibit MAO-A, which is responsible for the
intracellular breakdown of 5HT and NA (MAO-B breaks down dopamine, and is
inhibited by selegiline, an adjunctive treatment for Parkinson’s disease). The major
examples are phenelzine, tranylcypromine and iproniazid. In contrast to the effects of
the TCA’s, MAO, and therefore the MAOI’s, do not play a role in the uptake of the
transmitter. Instead, they increase the intracellular concentrations of the amine, which
allow it to leak out. They have the same delayed activity as the TCA’s, causing
delayed downregulation of β adrenoceptors and 5HT2 receptors.

These drugs have traditionally been less popular than the reuptake inhibitors. There
are a number of side effects and potentially toxic drug interactions. Either hyper or
hypotension can occur, the former due the indirect sympathomimetic action of the
MAOI, and the latter due to the accumulation of the inhibitory dopamine in the
sympathetic ganglia. If the analgesic pethidine is given together with MAOI, severe
hyperpyrexia, restlessness, coma and hypertension can result (Rang and Dale). The
main problem with the MAOI’s is due to the effects of tyramine, found in cheese and
wine. This would normally be broken down by MAO in the gut the wall, but this has
been inhibited, so tyramine reaches the systemic circulation. Upon arriving at the
noradrenergic neurons, it displaces noradrenaline from vesicles into the cytoplasm.
But in the absence of MAO, noradrenaline leaks out from the neuron. This causes
acute severe hypertension, the main manifestation of which is a throbbing headache.
Since foods can vary a lot in their tyramine content, it is important to provide patients
who would use this drug with a list of foods to avoid. Another way round this
problem is to use a reversible MAO inhibitor, such as moclobemide. These do not
have this effect: they are displaced from the enzyme by any primary amine such as
tyramine which might be in the diet.

Tetracyclic antidepressants are a more recent innovation, an example of the second

generation anti depressants. Mianserin was the first to be developed. It does not
inhibit MAO, does not inhibit amine reuptake, and lacks any cardiotoxic effects or
anticholinergic action. It was however sedative, via an antihistamine action, and
caused postural hypotension via α1 receptors. So it was abandoned in favour of
Mirtazepine, which has very similar pharmacological therapeutic effects.

Mirtazepine is a Noradrenaline and Selective Serotonin Antagonist. Despite the

“selective” nomenclature, it actually has very broad pharmacological effects. It has
direct effects on the 5HT2A and 5HT3 receptors, and indirect effects on 5HT1A
receptors. I have already explained the usefulness of 5HT2A antagonism in increasing
5HT release. Similarly, mirtazepine antagonises α2 receptors to increase NA release,
as well as 5HT release. The 5HT3 antagonism seems to reduce nausea and anxiety that
sometimes results from 5HT increase by SSRI’s. In addition, blocking these
postsynaptic receptors frees the 5HT to act exclusively on the 5HT1A receptors, which
is presumably the receptor by which the useful antidepressant properties occur.
Mirtazepine seems to alleviate depression somewhat more rapidly than the traditional
drugs.

St John’s Wort (Hypericum) is not a licensed drug in Europe, except in Ireland, but is
a powerful antidepressive available over the counter. It is very widely used, and there
are several studies demonstrating its increased effectiveness in treating mild
depression against standard anti depressants. The main active ingreadiant is
hyperfolin, which is uptake inhibitor of NA, 5HT and dopamine. It also antagonises
glutamate receptors. One danger is that it interacts with cytochrome p450, exerting
some undesirable drug interactions that could potentially be lethal (if the patient does
not tell their doctor that they are also taking St John’s Wort).

Electroconvulsive therapy (ECT) is another important line of treatment for

depression. This was another serendipitous discovery, since it has been used for over
50 years to treat many different psychological ailments, without anyone knowing how
it works. The patient is artificially ventilated, paralysed, and electrical stimulation is
via electrodes placed on either side of the head, although nowadays transcranial
magnetic stimulation is preferred. Unilateral ECT is more effective for unilateral
depression, preferably the dominant hemisphere for minimisation of side effects,
while oddly enough bilateral ECT is more effective for bilateral depression!

Just like antidepressants, ECT seems to take 2-3 weeks to have significant effects.
With chronic ECT treatment, NA and 5HT levels are increased, α2 receptor and
number are decreased, as are dopamine autoreceptors. These are much the same
changes as seen on application of antidepressants, and indeed 5HT2 receptor activity
is enhanced (although I am not sure of the effects on receptor density), while β2
activity is decreased. The mechanism of how ECT causes these changes in
neuromodulators levels I do not know.

Bipolar disorder is a somewhat different condition, involving oscillations between

depression (as described above) and mania, with elevated mood, irritability, flight of
ideas (of the Napoleonic variety: Rang and Dale), and grandiosity. People normally
get either depression or bipolar disorder, very rarely will one lead to the other. Twin
studies have suggested that there is a significant genetic component to bipolar
disorder which is not seen in standard depression, although any such genetic basis is
probably polygenic. No genes have yet been identified. Once again, the amine theory
has a view, suggesting that the changes in depressive episodes are the same as
discussed above, while the mania results from excess 5HT and NA. NA has been
particularly studied, with increased NA levels during manic phases. 5HT uptake
seems to be increased in mania, and normalised by treatment and recovery. Certainly,
some standard antidepressants, if used naively, can tip bipolar depressives from
depression into mania. In addition to this, there seems to be excessive activation of the
dopaminergic system, since the dopamine antagonists (neuroleptics) attenuate the
symptoms of mania, and dopaminomimetics such as amphetamine can lead to mania
in bipolar patients during remission. There also seems to be underactivation of the
GABA system.

Lithium salts are without a doubt the most effective treatment for mania. Although
they have been known for a long time, having come into pharmacological use in 1949,
and having been used widely since the 1970’s9, little is understood about their mode
of action. It is used prophylactically to stabilise mood, taking about 3-4 weeks to exert
its maximum effects, though it is also used as an adjunct to treatment in severe
unipolar depression, as well as to stabilise acute episodes of mania. Plasma

9
Without wishing to be at all cynical, it is said that the reason for this delay was the pharmaceutical
industry’s unwillingness to investigate the properties of a drug that could be dug out of the ground!
concentrations of between 0.6 and 1.2 mMol are useful; above 1.5mMol can be
dangerous and so it is important to monitor this carefully.

As a monovalent cation, lithium can mimic the effects of Na and K. It is not pumped
out by the Na/K/ATPase, and so will tend to accumulate inside cells, displacing Na
and K. It seems to slow the repolarisation of the nerve cells, though it is not clear
what relationship if any this has to its clinical effects. Cations in general often have
effects on all aspects of biogenic amine handling, and lithium is no exception. It has
well defined effects on receptor sensitivities, decreasing the sensitivity of pre and post
synaptic dopamine receptors (therefore accounting for mood stabilisation, possibly),
and increased reuptake of NA while inhibiting its release. According to the amine
hypothesis, at least, this will tend to produce an anti manic effect. Lithium also
decreases the sensitivity of the β2 adrenoceptor, just like the antidepressants discussed
above.

The common theme of these altered receptor sensitivities is decreased coupling to

cAMP via the Gs pathway. ADH and TSH actions on their receptors are inhibited by
lithium due to this. Rang and Dale state that this is not a pronounced effect in the
brain, but given the effects on β2 and the postsynaptic dopamine receptor D1, it
probably does have some role to play. If this however is correct, perhaps we should be
looking for a drug which has the desirable effects of lithium, but which does not affect
the Gs-cAMP-PKA pathway. Lithium blocks the phosphatidyl-inositol pathway at the
point where inositol phosphate is hydrolysed to free inositol (Rang and Dale), thus
causing depletion of membrane bound phosphatidyl-inositol (since for example DAG
and IP3 cannot be recycled to form PIP2), and thus blockage of many receptors.

Lithium thus has very wide ranging actions, and an enormous range of side effects.
The reduction of sensitivity to TSH and ADH have already been mentioned, and due
to the loss in ADH sensitivity, there is a hyper aldosteronism which presumably can
lead to hypokalaemia. There is also polyuria and increased thirst. Increase in
parathyroid hormone can lead to hypercalcaemia. Weight gain occurs in up to 60% of
patients. Ironically, other side effects cause nausea, diarrhoea and vomiting.

Thus although lithium is the most widely accepted anti manic drug currently
available, it has a host of side effects and a poorly understood mode of action. The
same accusation could be levelled at the antidepressants used to treat unipolar
depression. Thus more research is needed into the pathologies underlying this very
common problem, which will hopefully elucidate more effective ways of treating it.