Second edition

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626 Idiopathic psychotic, mood, and anxiety disorders
some may believe that all are dead, that death has finally
achieved complete dominion over the world. Auditory hallucinations
may also occur and generally reflect the patients’
delusions. Voices may accuse them of crimes or sins, or
announce that their well-deserved punishment is at hand.
Visual hallucinations occasionally occur, and patients may
see corpses or accusatory spirits. In some cases patients may
develop stuporous catatonia (Starkstein et al. 1996).
Other symptoms seen during a minority of depressive
episodes include anxiety attacks (Van Valkenburg et al.
1984) and what have been called ‘anger attacks’, in which
generally hostile and irritable patients occasionally experience
episodes of violence and autonomic arousal (Fava et al.
1993). Obsessions and compulsions may also appear: a particularly
common obsession is the ‘horrific temptation’ to
use a knife or gun to kill a loved one, and a consequent overwhelming
necessity to rid the house of all potential weapons
and to avoid any contact with them outside the house.
Course
Major depressive disorder is a relapsing and remitting illness
(Thase 1990), characterized in most patients by the
recurrence of depressive episodes throughout their lives, in
between which they return to a more or less normal mood.
As noted earlier, in about 50 percent of cases, depressive
episodes will undergo a spontaneous remission within
6–12 months. The duration of the interval between successive
episodes ranges widely, from as little as 1 year up to
decades, with an overall average of about 5 years. In general,
however, with repeated episodes the interval between
episodes tends to shorten, and the episodes themselves
tend to lengthen, such that, over a very long period of time,
successive episodes may eventually ‘merge’ to create a
chronic, non-remitting condition.
Recently, much attention has been focused on patients
whose depressive episodes seem entrained to the changing
seasons. In patients with this seasonal pattern of illness,
depressive episodes appear to occur far more commonly in
the fall or winter than in the spring or summer.
Etiology
Hereditary factors appear to play a role: the prevalence of
major depression is higher in the relatives of patients than
of control subjects, and the monozygotic concordance rate
is significantly higher than the dizygotic one (McGuffin
et al. 1996). To date, however, genetic studies have not
identified genes or loci that may be confidently associated
with this illness, indicating in all likelihood that, from a
genetic point of view, this is a complex disorder, involving
multiple genes and multiple modes of inheritance.
Hereditary factors, although clearly important, do
not appear to provide a complete account, and environmental
factors also seem to play a role. Among the various
environmental events proposed, it appears that early childhood
loss may be the most important. Events may also
serve as precipitants for episodes in adult life; however, as
noted earlier, the importance of precipitants fades with
successive episodes to the point where, over long periods of
time, episodes become, as it were, autonomous.
There is abundant evidence for endocrinologic disturbances
in depression, all of which point to disturbances in
the hypothalamus. Within the hypothalamus, for example,
the level of messenger RNA for CRH in the paraventricular
nucleus is elevated (Raadsheer et al. 1995), as is the cerebrospinal
fluid (CSF) level of CRH (Nemeroff et al. 1984);
consistent with this, the low-dose DST test is generally positive
(Carroll et al. 1968, 1976). The thyroid axis also shows
disturbances: the CSF level of TRH is elevated (Banki et al.
1988), and, consistent with this, the response of TSH to
exogenous TRH is blunted (Prange et al. 1972).
Abnormalities in brainstem structures responsible for
REM sleep are suggested by the fact that REM sleep latency
is reduced in depression (Hauri et al. 1974; Rush et al.
1986), and by the response to cholinergic agents.
Normally, REM sleep may be induced by cholinergic stimulation;
however, in patients with major depressive disorder
the latency to REM sleep with such cholinergic agents
as arecoline (Gillin et al. 1991) and donepezil (Perlis et al.
2002) is shorter than in control subjects.
The undoubted success of antidepressant medications has
focused attention on biogenic amines. Given that all antidepressants
have effects on either noradrenergic or serotoninergic
functioning, it appears reasonable to assume that there
is a complementary disturbance in these amines in patients
with major depressive disorder. Despite enormous research
efforts, however, it has been difficult to isolate definite abnormalities
here. One notable exception involves the effects of
tryptophan depletion. Tryptophan is the dietary precursor of
serotonin and, in patients with an antidepressant-induced
remission of depression, tryptophan depletion is promptly
followed by a relapse of depressive symptoms (Aberg-Wistedt
et al. 1998; Delgado et al. 1990; Smith et al. 1997).
Relatively speaking, neuropathologic studies are in their
infancy in this disorder. Some studies have suggested
changes in the dorsolateral prefrontal cortex; however, in
my opinion the endocrinologic and sleep abnormalities
point rather to the diencephalon or brainstem as the most
likely sites for any changes. In this regard, several, albeit
preliminary, findings have been reported, including the
following; an increased number of neurons in the
mediodorsal nucleus of the thalamus (Young et al. 2004);
an overall decreased number of neurons in the paraventricular
nucleus of the hypothalamus (Manaye et al.
2005) with a relative increase in the number of CRH-containing
neurons in the same nucleus (Bao et al. 2005).
Integrating all of the foregoing findings into a coherent
theory is problematic and involves some speculation. With
this caveat in mind, however, it may be reasonable to propose
that major depressive disorder represents an interaction
between certain environmental events and an inherited