Depression is a chronic and recurrent disorder that is associated with significant physical and social dysfunction;still, it remains under-diagnosed and under-treated in all age groups.
It is a common clinical problem seen in primary care, with 70% of prescriptions for Antidepressant now written by primary care physicians.
THE NATURE OF DEPRESSION |
Depression is the most common of the affective disorders (disorders of mood rather than disturbances of thought or cognition); it may range from a very mild condition, bordering on normality, to severe (psychotic) depression accompanied by hallucinations and delusions |
The symptoms of depression include emotional and biological components:
Ø emotional symptoms:
o misery, apathy and pessimism
o low self-esteem: feelings of guilt, inadequacy and ugliness
o indecisiveness, loss of motivation.
Ø biological symptoms:
o retardation of thought and action
o loss of libido
o sleep disturbance and loss of appetite
COMMON FEATURES OF DEPRESSION
Core symptoms
Ø Low mood
Ø Loss of interest (anhedonia)
Ø Fatigue or reduced energy
Additional features
Ø Negative cognition (excessive guilt, hopelessness, and worthlessness)
Ø Suicidal ideation
Ø Disturbed sleep
Ø Change in appetite and weight
Ø Inattention and poor memory
Ø Psychomotor retardation or agitation
Diagnostic features
Ø Persistent symptoms for more than 2 weeks
Ø ICD*-10 classification requires two of the three core symptoms plus additional symptoms
Ø DSM†-IV classification requires either low mood or anhedonia plus additional symptoms
Ø Atypical symptoms like hypersomnia, increased appetite, weight gain also present in a proportion of depressed patients
Ø Anxiety symptoms are also commonly present in Depression
There are two distinct types of depressive syndrome
Ø Unipolar depression
Ø Bipolar depression
THEORIES OF DEPRESSION |
THE MONOAMINE THEORY |
The main biochemical theory of depression is the monoamine hypothesis, proposed by Schildkraut in 1965, which states that depression is caused by a functional deficit of monoamine transmitters at certain sites in the brain, while mania results from a functional excess. CURRENT THERAPIES AND DRUGS FOR DEPRESSION: |
ANTIDEPRESSANT DRUGS
Monoamine uptake inhibitors 1. Tricyclic (TCA) Inhibition of NA/5-HT reuptake Sedation Ventricular dysrhythmias 'First-generation' antidepressants, still very widely used, though newer compounds generally have fewer side-effects and lower risk with overdose Anticholinergic effects (dry mouth, constipation, blurred vision, urinary retention, etc.) High risk in combination with CNS depressants Postural hypotension Seizures Impotence Interaction with CNS depressants (esp. alcohol, MAOIs) Imipramine Non-selective As above As above t1/2 4-18 h; converted to desipramine Desipramine NA-selective As above As above t1/2 12-24 h Amitriptyline Non-selective As above As above t1/2 12-24 h; converted to nortriptyline Widely used, also for neuropathic pain (Ch. 40) Nortriptyline NA-selective (slight) As above As above Long t1/2 24-96 h Long duration Less sedative Clomipramine Non-selective As above As above t1/2 18-24 h Also used for anxiety disorders 2. Selective serotonin (5-HT) reuptake inhibitors (SSRI)All highly selective for 5-HT Nausea, Low risk in overdose, but must not be used in combination with MAOIs Side Effectes : Diarrhoea , Agitation, Insomnia , Anorgasmia, Inhibit metabolism of other drugs, so risk of interactionsFluoxetine Long t1/2 24-96 h Fluvoxamine t1/2 18-24 h Less nausea than other SSRIs Paroxetine t1/2 18-24 h Withdrawal reaction Citalopram t1/2 24-36 h Sertraline t1/2 24-36 h 3. MiscellaneousMaprotiline Selective NA uptake inhibitor As TCA, no significant advantages As TCA Long t1/2 ∼40 h No significant advantages over TCAs Reboxetine Selective NA uptake inhibitor Dizziness Insomnia Anticholinergic effects Safe in overdose. (low risk of cardiac dysrhythmia) t1/2 ∼12 h Safer and fewer side-effects than TCA Venlafaxine Weak non-selective NA/5-HT uptake inhibitor. As SSRIs Safe in overdose Short t1/2 ∼5 h Claimed to act more rapidly than other antidepressants, and to work better in 'treatment-resistant' patients Also non-selective receptor-blocking effects Withdrawal effects common and troublesome if doses are missed St John's wort (active principle: hyperforin) Weak non-selective Few side-effects reported Risk of drug interactions through enhanced drug metabolism (e.g. loss of efficacy of ciclosporin, antidiabetic drugs) t1/2 ∼12 h Freely available as crude herbal preparation. Effective in clinical trials. Similar to other antidepressants, but fewer acute side-effects. Risk of serious drug interactions NA/5-HT uptake inhibitor. Also non-selective receptor blocking effects Monoamine oxidase inhibitors (MAOIs)Inhibit MAO-A and/or MAO-B Earlier compounds have long duration of action because of covalent binding to enzyme Phenelzine Non-selective 'Cheese reaction' to tyramine-containing foods (see text) Many interactions (TCAs, opioids, sympathomimetic drugs)-risk of severe hypertension due to cheese reaction t1/2 1-2 h Anticholinergic side-effects , Duration of action long because of irreversible binding ,Hypotension,Insomnia , Weight gain , Liver damage (rare) Tranylcypromine Non-selective As phenelzine As phenelzine t1/2 1-2 h Duration of action long because of irreversible binding Isocarboxazid Non-selective As phenelzine As phenelzine Long t1/2 ∼36 h Moclobemide MAO-A selective Nausea Interactions less severe than other MAOIs; no cheese reactions reported t1/2 1-2 h Safer alternative to earlier MAOIs Short-acting Insomnia, , Agitation Miscellaneous antidepressants Bupropion Not known. Dizziness Safe in overdose t1/2 ∼12 h Used mainly in depression associated with anxiety, Weak dopamine uptake inhibitor , Anxiety,Seizures Trazodone Weak 5-HT uptake inhibitor. Sedation Safe in overdose t1/2 6-12 h Nefazodone and mianserin are similar Also blocks 5-HT2 - and H1-receptors (enhances NA/5-HT release) Hypotension, Cardiac dysrhythmias Mirtazapine Blocks α2, 5-HT 2- and 5-HT3-receptors Dry mouth No serious drug interactions t1/2 20-40 h Claimed to have faster onset of action than other antidepressants, Sedation , Weight gain |
- TCA and SSRI act by inhibiting uptake of noradrenaline and/or 5-HT by monoaminergic nerve terminals, thus acutely facilitating transmission.
- MAOIs inhibit one or both forms of brain MAO, thus increasing the cytosolic stores of noradrenaline and 5-HT in nerve terminals. Inhibition of MAO-A correlates with antidepressant activity. Most are non-selective; moclobemide is specific for MAO-A.
- Mode of action of 'atypical' antidepressants is poorly understood.
- All types of antidepressant drug take at least 2 weeks to produce any beneficial effects, even though their pharmacological effects are produced immediately, indicating that secondary adaptive changes are important.
- The most consistent adaptive change seen with different types of antidepressant drug is downregulation of β- and α2-adrenoceptors, as well as 5-HT2-receptors. How this is related to therapeutic effect is not clear
MOOD-STABILISING DRUGS |
Mood-stablising drugs are used to control the mood swings characteristic of manic-depressive (bipolar) illness. Lithium is most commonly used, but recently antiepileptic drugs such as carbamazepine  , valproate and gabapentin, which have fewer side-effects and problems than lithium, have also proved efficacious. |
MEASUREMENT OF ANTIDEPRESSANT ACTIVITY
Various behavioural tests have also been used (see above), though there is no animal model that satisfactorily resembles depressive illness in humans. Some of the most useful tests are the following.
- Potentiation of noradrenaline effects in the periphery Stimulation of sympathetic nerves or administration of noradrenaline causes contraction of smooth muscle, which is enhanced if the noradrenaline reuptake mechanism of the nerve terminal is blocked (see Ch. 11). This test gives positive results with monoamine uptake inhibitors but does not reveal MAOI or atypical antidepressant activity.
- Potentiation of the central effects of amphetamine Amphetamine works partly by releasing noradrenaline in the brain, and its actions are enhanced both by MAOI and by uptake inhibitors. Some atypical antidepressants also give a positive response, making it a useful test for predicting activity in humans.
- Antagonism of reserpine-induced depression Reserpine depletes the brain of both noradrenaline and 5-HT, causing various measurable effects (hypothermia, bradycardia, reduced motor activity, etc.), which are reduced by antidepressant drugs. This test also reveals activity among the atypical antidepressants.
- Block of amine uptake in vitro Among TCA there is a fairly good correlation between antidepressant activity and potency in inhibiting noradrenaline or 5-HT uptake, but MAOI and many other antidepressants have no effect
- Animal models of depression include,
- learned helplessness model
- reversal of reserpine-induced behavioural syndrome
- mother-infant separation in primates.
None is a good model for human depressive illness, but they are the best available for testing new drugs
ELECTROCONVULSIVE THERAPY :
ECT in humans involves stimulation through electrodes placed on either side of the head, with the patient lightly anaesthetised, paralysed with a neuromuscular-blocking drug so as to avoid physical injury, and artificially ventilated. More recently, a technique involving transcranial magnetic stimulation, which does not require these precautions, has been introduced. Controlled trials have shown ECT to be at least as effective as antidepressant drugs, with response rates ranging between 60 and 80%; it appears to be the most effective treatment for severe suicidal depression. The main disadvantage of ECT is that it often causes confusion and memory loss lasting for days or weeks.
NEWER TARGETS AND DRUGS FOR DEPRESSION:
AGENTS INTERACTING WITH NON-CATECHOLAMINE NEUROTRANSMITTER SYSTEMS:
Antidepressants/mood stabilizers that impact primarily glutamate receptors such as NMDA receptor antagonists, metabotropic glutamate receptor (mGluR) agonists and antagonists, and positive modulators of a-amino-3-hydroxy-
5-methyl-4-isoxazolepropionic acid (AMPA) receptors havedemonstrated antidepressant-like properties, with potential common downstream mechanisms of action
NMDA Receptor Antagonists (Major Depressive Disorder And Bipolar Depression)
There is substantial evidence that NMDA receptor antagonists have antidepressant properties (Krystal, 2007). Chronic treatment with NMDA antagonists such as MK-801 and AP-7 resulted in antidepressant-like behavioral effects in models such as chronic mild stress, learned Helplessness, footshock-induced aggression, and olfactory bulbectomy (reviewed in Paul and Skolnick, 2003). Chronic, but not acute, treatment with NMDA antagonists also resulted in reductions in density of forebrain b-adrenoreceptors (Paul et al, 1992; Maj et al, 1993) and 5-HT2 receptors (Papp et al, 1994)
AMPA Receptor Potentiators/AMPAKINES
(Major Depressive Disorder)
AMPA receptors are a subfamily of ionotropic glutamate receptors that mediate the fast component of excitatory neurotransmission, and which, like NMDA receptors, are involved in learning and memory. Several AMPA receptor potentiators in development have demonstrated antidepressant effects in animal models of depression, including exposure to inescapable stressors, the forced swim test, the tail-suspension-induced immobility test, and learned helplessness models
NEUROPEPTIDES AS THERAPEUTIC TARGETS FOR MAJOR DEPRESSION
Neuropeptides are short-chain amino acids that act as neurotransmitters in brain circuits implicated in mood and anxiety regulation. Below we review two classes of neuropeptide receptor antagonists that are well represented in phase II and III RCTs of unipolar depression : (1) CORTICOTROPIN-RELEASING FACTOR-1 (CRF1) RECEPTOR, also known as corticotropin-releasing hormone (CRH), antagonists:
Over 20 years of preclinical research have suggested that the 41-amino-acid peptide CRF is an important mediator of the stress response, coordinating the neuroendocrine, utonomic, immune, and behavioral responses to stress, while hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis has been associated with subgroups of patients with major depression
(2) NEUROKININ (NK) RECEPTOR ANTAGONISTS:
Substance P is the most abundant brain tachykinin (a class, which includes NK A and B among others), and is the endogeneous ligand for the neurokinin 1 (NK-1) receptorGenetic or pharmacologic blockade of NK-1 receptors were observed to induce many of the same long-term neural effects as standard antidepressants on cell signaling molecules such as BDNF and hippocampal neurogenesis
PROTEIN KINASE C-SIGNALING CASCADE (BIPOLAR DISORDER)
PKC is a shared biochemical target for the actions of chronic lithium and valproate. PKC is highly enriched in the brain, where it plays a major role in regulating both preand postsynaptic aspects of neurotransmission. PKC is now known to exist as a family of closely related subspecies, has a heterogeneous distribution in brain (with particularly high levels in presynaptic nerve terminals), and plays a major role in the regulation of neuronal excitability, neurotransmitter release, and long-term alterations in gene expression and plasticity
SYNUCLEINS:
Drugs currently used to treat depression target the regulatory process for neurotransmitters, and while effective in some cases, do not appear to work in other cases. Previous studies have suggested that synucleins, a family of small proteins in the brain, are key players in the management of neurotransmitters -- specifically, alpha- and gamma-synuclein. Also, researchers had found elevated levels of gamma-synuclein in the brains of both depressed animals and humans. In a new study, they observed increased depressive-like behavior in mice where gamma-synuclein acts alone to regulate neurotransmitters, confirming earlier studies by this group.
"These findings show the importance of, and clarify a functional role for, gamma synuclein in depression and may provide new therapeutic targets in treatment of this disease," said Adam Oaks, a student researcher in the Laboratory of MolecularNeurochemistry at GUMC.
Read more about Newer Drugs for Depression and Anxiety Click here
REFERENCES:
1. YK Wing, Recent advances in the management of depression and Psychopharmacology ,HKMJ 2000;6:85-92
2. Sanjay J Mathew, Husseini K Manji and Dennis S Charney ,Novel Drugs and Therapeutic Targets for Severe Mood Disorders; Neuropsychopharmacology (2008), 1–13.
3. JOHANNE ROSE L.AC. A; Natural Approach to Depression , CLINICAL NUTRITION INSIGHTS Vol.6, No. 4
4. Joseph A. Lieberman III, History of the Use of Antidepressants in Primary Care Companion, J Clin Psychiatry 2003;5[suppl 7]:6–10
5. Madhukar H Trivedi, MD and Ella J Daly, MB, MRC ; Psych Treatment Strategies and Tactics for Treatment-resistant Depression, © T O U C H B R I E F I N G S 2 0 0 7.
6. A report byThe British Psychological Society ;Division of Clinical psychology recent advances in understanding mentalillness and psychotic experiences
By: Krishna kumar gokavarapu
BITS Pilani (M.Pharm)
Tags:
Pharmacology