CENTER ON BEHAVIORAL MEDICINE

ADDITIONAL MATERIAL

RELATED PAPERS
Related Papers Menu

Mood Disorders and Various Causes and Treatments

Permission graciously given by the author to reproduce this paper: 
 

Mood Disorders and Various Causes and Treatments

Kane
2006

          Mood disorders, also referred to as depressive disorders, are disturbances of emotion that affect an individual’s entire psychic life (IOM, 1994). Depressive disorders are quite common and tend to co-occur with other serious mental disorders, including substance abuse, anxiety disorders, and schizophrenia. Mood disorders are strongly associated with suicide, one of the leading causes of death in adults and adolescents, and with far-reaching impairments in functioning not only for the depressed individual but also for family members (Cicchetti & Toth, 1998).

            There are several types of mood disorders including major depressive disorder (unipolar depression), dysthymia, bipolar disorder, and cyclothymia. Depression is characterized by feelings of sadness or despair that last for at least two weeks and very often impair a person’s ability to carry out their normal activities of daily life. Dysthymia resembles depression but has a longer and more consistent duration. Bipolar disorder is characterized by alternating cycles of lows (depression) and highs (mania). Cyclothymia is marked by cycles of low-level depression and hypomania - which is typically shorter in length and less severe than mania.

            Research is increasingly showing that unipolar and bipolar mood disorders are continuous entities within the complete mood spectrum. This spectrum runs continuously from unipolar depression to schizo-bipolar disorder with anxiety disorders running across the gamut. However, many professionals contest this claim. Some maintain that bipolar disorder, for example, may actually be biochemically closer to schizophrenia than (unipolar) depression. There are also forms of mood disorder that are specific to women, related to physiological events such as pregnancy, giving birth or menopause - these include Premenstrual Dysphoric Disorder and Postpartum Psychosis (National Mental Health Information Center, 2006).

            Bipolar disorder occurs equally in women and men, but women are two times as likely as men to experience a major depressive disorder (American Psychological Association, 2000). These disorders can take a tremendous toll on a person’s ability to work, to sustain relationships, and to perform day-to-day activities. It is important that mood disorders be accurately diagnosed and treated because proper treatment not only helps improve the symptoms of these disorders, but can also restore the person to a better quality of life. Depression is an under-treated condition resulting in a high degree of disability (Ebmeier, Donaghey, & Steele, 2006).

            Clinical depression refers to a prolonged feeling of sadness that becomes overwhelming and prevents a person from functioning normally in their life; and is characterized by a low mood lasting two weeks or more and accompanied by changes in sleep, energy, appetite or concentration. Feelings of guilt and inadequacy are common (American Psychological Association, 2000). Depression can impact all aspects of a person’s life and in severe cases persons may experience thoughts of suicide. There are many circumstances that can contribute to developing depression including: genetics (a history of depression in the family); serious illness or medical conditions; grief from the loss of a loved one; life changes (such as divorce, job loss, etc.); abuse (physical, mental, emotional, or sexual); substance abuse; and side effects of medication (Cicchetti & Toth, 1998). Sometimes depression actually has no precipitating event and happens surprisingly and without warning. Without treatment, depression can last for weeks to years and most often occurs several times over the course of a lifetime. Treatment may vary from person to person, but usually includes a combination of education, medication and psychotherapy (National Mental Health Information Center, 2006).

            Bipolar disorder, which formerly was known as manic-depressive illness, is a brain disorder that causes extensive changes in a person’s mood, energy, and ability to function. Bipolar I disorder is the most severe form of the illness and consists of alternating periods of mania and depression, In comparison, Bipolar II disorder consists of alternating periods of recurrent depression and less intense episodes of mania, called hypomania. Extreme mood swings punctuated by periods of generally even-keeled behavior characterize this disorder. Bipolar disorder tends to run in families, and typically begins in the mid-twenties and continues throughout life. Without treatment, people who have bipolar disorder often go through devastating life events such as marital breakups, job loss, substance abuse, and suicide. Alcohol and drug abuse are common among people suffering from bipolar disorder and there may also be an increased tendency for anxiety disorders as well. People often suffer for years before bipolar disorder is properly diagnosed and treated. Once diagnosed, most people can respond to treatment that combines medication, education, therapy, and support. The goals of treatment of Bipolar disorder are to stabilize the acute episode and to prevent the recurrence of future episodes (National Mental Health Information Center, 2006).

Causes of mood disorders

            Substantial evidence suggests that there are two important shifts in the epidemiology of major depression - increases in cumulative lifetime rates and a considerable shift to an earlier age of onset. Bipolar disorder occurs less frequently than major depression with the reported lifetime prevalence being around 1% for both men and women. There is a consistent younger age of onset for bipolar disorder than for depressive disorders. The median age of onset of bipolar disorder is said to be 18 for men and 19 for women (Bland, 1997).

            In the past, doctors believed that mood disorders were the result of thoughts or emotions that were troubling for a person. More recently, experts realize that there can be several factors working together that will lead a person to become depressed. The three most important of these are biological, genetic, and environmental factors. Genetic causes are the result of what you inherit from your parents. Environmental factors (also called emotional factors) result from stressful emotional situations, such as a lack of loving parents or the death of a parent during childhood. Biological causes are due to changes in the chemistry of the brain, such as fluctuations in the levels of important hormones. A mood disorder can occur as a result of a combination of these three factors.

Genetic factors

      Ebmeier, Donaghey, & Steele (2006) state that there is no doubt that genetic factors have an important role in the etiology of depression; and further believe that depression with recurrent episodes and early onset may be associated with familial aggregation. Heritability of depression has been estimated to range from 30 – 40%. Recent genetic research also supports earlier studies reporting family links in depression. Many researchers, including Weissman, Warner, Wichramaratne, Moreau, & Olfson (1997) have found that there is a greater prevalence of mood disorders in the relatives of depressed persons than in the general population and an even higher probability of the disorder among relatives who are more closely related. For example, if one identical twin suffers from depression or bipolar disorder, the other twin has a 70 percent chance of also having the illness. Other studies that looked at the rate of depression among adopted children support this finding. Depressive disorders among adoptive family members had little effect on a child's risk of depression; however, the disorder was three times more common among adopted children whose biological relatives suffered depression.

      Although genes may influence the development of early structures (such as receptors for neurotransmitters) that influence normal and pathological temperament, later gene activation and deactivation may modify those same structures again. Steingard, et al (1996) found decreased frontal-lobe volume and increased lateral ventricular volume in the brains of hospitalized children with depressive disorder. These findings were congruent with similar results using the same MRI techniques with adults with depressive disorders. Other genetic variations among children and adolescents with depressive disorder include a change in growth hormone, prolactin secretion and serotonergic functioning (Birmaher, et al., 1997). Difficulties have been observed in hypothalamic-pituitary-adrenal (HPA) axis regulation in adults with depressive disorders (Gold, Goodwin, & Chrousos, 1988b).

      Cicchetti & Toth (1998) explain that lateralization of neurotransmitter systems and hemispheric asymmetries influence arousability to stimulation and individual differences in emotion processing. The right hemisphere is sensitive to change through the interaction of noradrenergic and serotonergic systems, and alerts the brain to novelty in the environment, and is then associated with general arousal and brain activation. The left hemisphere is biased toward redundancy and is dominated by dopaminergic and cholinergic systems and is influenced by novelty to maintain behavior in the face of change. Electroencephalogram (EEG) studies suggest that negative emotional states correspond to relatively less left-frontal or greater right-frontal activation or both, whereas positive states correspond to the opposite pattern of activation. Evidence has been found that infants of depressed mothers displayed reduced left-frontal brain activation and greater relative right-frontal EEG unevenness. Dawson (1992) and her colleagues interpreted these findings to imply that both maternal depressive symptoms and attachment security are reflected in an infant’s frontal lobe functioning and emotional behavior and that a genetic diatheses for depression and the quality of care giving experienced by a child both have an impact on neurobiological development. Basically, there seems to be no absolute on the exact mechanism that triggers depressive illness. Probably there is no single genetic cause for the disorder.

Environmental factors

      Depressive disorders present a particularly important area of interest because of the diverse systems that influence the causes of these disorders. Abnormalities in cognitive, socioeconomic, familial, and biological areas are present in varying degrees in persons suffering from depressive disorders. In a depressed individual there is either an incoherent organization among these areas or an organization of pathological structures which is referred to as depressotypic organization. Depressotypic organizations evolve developmentally and may turn into depressive disorders at different points across the course of a lifetime (Cicchetti & Toth, 1998.) Of particular interest is the connection of depressive disorders to the development of a secure attachment relationship.

      The development of an attachment relationship with the primary caregiver during the final half of the first year of life is a primary and essential task that organizes developing affect, cognition, and behavior. The role of the caregiver is to provide a secure base that helps the infant to adapt and adjust arousal, and to sustain internal security (Bowlby, 1982). The attachment relationship with the primary caregiver is very important in shaping the way in which affect, cognition, and behavior are organized. Ainsworth (1978) identified three major types of attachment organization that are important for understanding the possible early formations of divergent organization that may lead to depressotypic organization. The traditional classifications include Type A - insecure-avoidant, Type B - securely attached, and Type C - insecure-ambivalent. Further investigation involving samples of high-risk children led to the identification of additional atypical insecure attachment patterns which involved a combination of both avoidant and resistant behaviors: Type A/C - a disorganized/disoriented pattern (Crittenden, 1988); Type D - includes a variety of undirected behavioral responses and unusual behaviors, such as freezing and hand flapping, exhibited when the caregiver is present (Main & Solomon, 1990).

      The traditional and atypical attachment classifications represent individual differences in the strategies that infants use to control emotions and behavior. Insecure attachment leads to problems in the organization of cognitive, affective, and biological systems, which may precipitate depressive episodes. Attachment-related features of a depressotypic organization may contribute to a proclivity to self-processes such as low self-esteem, helplessness, hopelessness and negative attributional biases, which have been linked to depressive disorders (Cicchetti & Toth, 1998).

      Many researchers have studied attachment in children of parents who suffer from mood disorders and have found that children of depressed parents are significantly more likely to develop insecure attachment to their caregivers. Insecurely attached children of depressed mothers exhibited withdrawal, passivity, and inhibited behavior; and have difficulty in self-development and affective functioning. Radke-Yarrow, Belmont, Mottelmann, & Bottomly (1990) found that mood-disordered mothers conveyed significantly more negative affect toward their children especially in regard to negativity about the child’s emotions. Kandel and Davies (1986) found that depression in adolescence was related to problems in the emotional relationship with parents. In late adolescence, an insecure attachment organization has been linked to higher levels of depressive symptoms (Kobak, Sudler, & Gamble, 1991). Among children of depressed parents, there is a heightened vulnerability for negative self-attributions with negative implications for risk of depressive disorders. The self-critical style of depressed parents appears to be transmitted to their children.

Biological factors

      People suffering from depression have imbalances of neurotransmitters, which interfere with the communication between brain cells. Two transmitters associated with depression are serotonin and norepinephrine. Scientists think a deficiency in serotonin may cause the sleep problems, irritability, and anxiety connected with depression; and that a decreased amount of norepinephrine, which regulates alertness and arousal, may add to the fatigue and depressed mood of the illness.

      Data clearly argue for a neurochemical origin of depressive disorders, basically that serotonergic and/or noradrenergic under activity is the key to the pathophysiology of clinical depression (Malhi, Parker, & Greenwood, 2005). Serotonin has been identified in midline neuronal nuclei at the pons level and upper brainstem, which contains more than half the 5-hydroxytryptamine (5HT) neurons found in the human central nervous system. Serotonin acts on at least a dozen receptor subtypes, two of which are coupled to binding proteins that sort out the biological responses of receptor interactions. There is evidence of receptor density changes and receptor abnormalities in clinical depression.

      Many studies implicate noradrenaline in clinical depression because it is central to a number of vegetative functions. Increased levels of noradrenaline have been found in the prefrontal cortex of depressed patients who have committed suicide (Garcia-Sevilla, Escriba, Ozaitta, et al., 1999). Noradrenaline also plays a critical role in the initiation and maintenance of anxiety states. Like serotonin, noradrenaline appears to contribute to both anxiety and depression. The fact that dual action antidepressants are more effective than SSRIs in melancholic depression (Malhi, Parker, & Greenwood, 2005) suggests that there is a greater noradrenergic dysfunction in this sub-type; and that non-melancholic depression occurs within the serotonergic systema and is modulated by noradrenergic mechanisms.

      Dopamine is abundant in some regions of the frontal cortex and is involved in movement disorders and psychosis. However, in depressed patients, the cerebrospinal fluid levels of the dopamine metabolite HVA are significantly reduced as compared with healthy individuals. Depletion of dopamine in the nucleus accumbens has been linked to “learned helplessness” and can be prevented by dopamine receptor agonists and antidepressants. Amphetamine-induced dopamine produces intense pleasure because mesolimbic dopaminergic nuclei form part of a central reward pathway, which is regulated by serotonergic projections to the nucleus accumbens (Koob, 1996).

      Obviously it is simplistic to assign the cause of a disease as multifaceted and diverse as mood disorders to the dysfunction of a few neurotransmitters. However, research strongly implicates serotonin, noradrenaline and dopamine in the pathophysiology of depressive disorders. Depressive disorders may be better understood, from a biological perspective, as reflecting variable dysfunction of the neurotransmitter regulation system as opposed to a simple increase or decrease in the activity of a particular neurotransmitter. These systems should be regarded as “regulators” of mood and emphasis must be on the dynamic processes that contribute to mood disorders (Malhi, Parker, & Greenwood, 2005).

Interesting theories

      There appears to be a common agreement that depressive disorders are associated with cognitive impairment. Episodic memory seems to be the main part of cognitive functioning that is susceptible to the negative effects of depression. These episodic memory impairments may be due to dysfunction of the hippocampus, since hippocampus atrophy has been shown in patients with depressive disorders. Of particular interest to clinicians is the finding that antidepressants can reverse these hippocampal changes (Ebmeier, Donaghey, & Steele, 2006).

      In spite of many years of research into bipolar disorder, its fundamental pathophysiology remains elusive. Pettigrew & Miller (1998) proposed that bipolar disorder is the result of a genetic predisposition for slow interhemispheric switching mechanisms that become “stuck” on the left (mania) or on the right (depression) sides of the cerebral hemisphere. Their studies focused on the mood shifts seen in bipolar disorder in terms of the cognitive style associated with the activated hemisphere: left-hemisphere activation being associated with confidence, elation or mania (according to the intensity) whereas an increasing degree of right-hemisphere activation would be associated with caution, apprehension or depression.

Medication in Depressive Disorders

            Drug treatments remain the mainstay of antidepressant therapy although antidepressants are not recommended for the initial treatment of mild depression (Ebmeier, Donaghey, & Steele, 2006). When depression becomes so pervasive and intense that normal functioning is impaired, antidepressant medication may be indicated. Many in the psychiatric field believe that depression causes and, in turn, is caused by an abnormality in the production of the neurotransmitters norepinephrine (noradrenaline) and serotonin plus a few others. Antidepressants are meant to increase the amount of serotonin or norepinephrine available to the brain to correct this imbalance.

      Many conditions that lower serotonin levels are associated with depression, suggesting that normal to slightly elevated serotonin levels tend to elevate mood and prevent depression. Serotonin has physiological roles in mood, sleep regulation, appetite, and both pain sensation and pain relief. Serotonin is concentrated in certain areas of the brain; the hypothalamus and midbrain have large amounts, while the cortex and cerebellum hold low concentrations. Like the majority of neurotransmitters, it is stored in nerve endings, and therefore is not exposed to inactivation by monoamine oxidases until it is released into the synaptic space between nerves. When a nerve containing serotonin fires, serotonin is released by exocytosis and can bind to any one of a chain of at least 14 distinct downstream serotonin receptors (5-HT receptors). Release of serotonin or other stored neurotransmitters can be induced by alkaloids such as reserpine, which have been used as tranquilizing agents in the treatment of nervous and mental disorders. Doses of serotonin create a type of sedation and other depressant conditions of the nervous system. Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase (MAO) inhibitors act by increasing the amount of active serotonin in nerve synapses in particular brain regions (Schwartz & Bruce, 2002).

      The brain is comprised of millions of interconnected brain cells called neurons. Messages travel along these cells like electricity down a wire, but when the message reaches the end of the neuron, it has to jump the gap (synapse) to the next cell or group of cells. This happens when the neuron releases tiny amounts of a chemical (neurotransmitter) into the gap between the nerve cells. The receiving neuron has a multitude of places on its surface which act like locks, for which the appropriate neurotransmitter is the key. These are called receptors. When enough of the neurotransmitter has locked on to these receptors, a nerve impulse is started in the new nerve. The message is then passed from one nerve to the next. The nerve has to recover in order to be ready to receive the next message, and to replenish its supply of the neurotransmitter in order to send the next message. The body removes the neurotransmitter from the receptors, and allows it to be taken back into the originating nerve. This process is called re-uptake (Carlton, 2002).

Selective Serotonin Reuptake Inhibitors (SSRIs)

      Multiple research and case studies attest to the fact that certain neurotransmitters are lacking in patients with depressive disorders. One of those is serotonin, also known as 5-hydroxytryptamine or 5-HT. One major type of antidepressant is the SSRIs (Selective Serotonin Re-uptake Inhibitors). The SSRIs slow down the process of returning the serotonin to the end of the neurons. This leads to the neurotransmitter staying in the vicinity of the receptors for longer, making it more likely that enough of the chemical will build up to set off the impulse in the next neuron. SSRIs work by allowing the body to make the best use of the reduced amounts of serotonin that it has at the time. In time, the levels of natural serotonin will increase, and the SSRI can be reduced and slowly withdrawn (Carlton, 2002).

      Selective serotonin reuptake inhibitors (SSRIs) are designed to allow the available neurotransmitter serotonin to be utilized more efficiently. A low level of utilization of serotonin is currently seen as one among several neurochemical symptoms of depression. Low levels of serotonin in turn can be caused by an anxiety disorder, because serotonin is needed to metabolize stress hormones. These medications increase the level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell. They have no or only weak effects on other monoamine transporters, thus having little direct influence on the level of other neurotransmitters. That distinguishes them from the older antidepressants - the tricyclics - so they are named selective. SSRIs are considered to be much safer than tricyclics (which inhibit the re-uptake of the transmitters norepinephrine, dopamine, and serotonin), since the toxic dose is much higher and they are said to have fewer and weaker side effects and drug interactions (Carlton, 2002).

   Prozac (fluoxetine) has received a large amount of publicity both pro and con since its release in 1988. It appears to be quite effective in the treatment of depression with fewer side effects than tricyclic antidepressants or the monoamine oxidase (MAO) inhibitors. It is also used to treat obsessive-compulsive disorders and panic disorder. Prozac is classified as an SSRI because it increases the amount of serotonin available to the nervous system. The amount needed to be effective varies widely from patient to patient and has to be adjusted. It generally takes two to four weeks for the full effect to be felt. The side effects are usually insomnia, nausea, diarrhea, headache, and nervousness. Most of the side effects are mild and will go away in a few weeks, Paxil (paroxetine and Zoloft (sertraline) are also classified as SSRIs and work to block serotonin uptake and have similar side effects to Prozac (Inaba & Cohen, 2000).

   Many drugs in this class are familiar in the USA through advertising, including the following:  (Trade names in parentheses)

escitalopram oxalate (Lexapro, Cipralex, Esertia)

citalopram (Celexa, Cipramil, Emocal, Sepram, Seropram)

fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR)) fluvoxamine maleate (Luvox, Faverin)         

parozetine (Paxil, Seroxat, Aropax, Deroxat, Paroxat)

sertraline (Zoloft, Lustral, Serlain)

dapoxetine (no known trade name)

Tricyclic Antidepressants    

    The exact mechanism of action is not well understood, however it is generally thought that tricyclic antidepressants work by inhibiting the re-uptake by nerve cells of the neurotransmitters norepinephrine, dopamine, or serotonin. Tricyclics may also posses  an affinity for muscarinic and histamine H1 receptors to varying degrees. Although the  pharmalogic effects occurs immediately, often the patient's symptoms do not respond for two to four weeks (Sweetman, 2002). Tricyclic antidepressants such as imipramine (Tofranil) and desipramine (Norpramine, Pertofrane) are thought to block reabsorption of neurotransmitters by the sending neuron, and so increase the activity of those biochemicals. This blocking effect forces the synthesis of more receptor sites for the neurochemicals. The delay in the creation of new receptor sites may account for the lag time in effecting a change in the patient’s mood.

    The tricyclics are very effective in treating patients with chronic symptoms of depression. The tricyclic antidepressants, can be dangerous if too many are taken so careful monitoring of not only compliance by the patient with prescribed dosage but also constant feedback from the patient as to the effects and side effects is also necessary. Major side effects are dry mouth, blurred vision, inhibited urination, hypotension, and sleepiness. These drugs are dangerous to the heart, especially if taken with stimulants, depressants, or alcohol. Patients must abstain from abusing drugs while being treated with tricyclic antidepressants (Inaba & Cohen, 2000). Antidepressant drugs in the tricyclic drug group include: 

            amitriptyline (Elavil, Endep, Tryptanol, Trepiline)

            clomipramine (Anafranil)

            desipramine (Norpramin, Pertofrane) dothiepin hydrochloride (Prothiaden)

            doxepin (Adapin, Sinequan)

            imipramine (Tofranil)

            ofepramine (Gamanil, Lomont)

            nortriptyline (Pamelor)

            protriptuline (Vivactil)

            trimipramine (Surmontil)

Monoamine Oxidase (MAO) Inhibitors

   Monoamine oxidase inhibitors (MAOIs) are very strong drugs that work by
blocking an enzyme that metabolizes the neurotransmitters norepinephrine and serotonin.  Due to potentially lethal dietary and drug interactions they are reserved as a last line of defense, used only when other classes of antidepressant drugs have been tried unsuccessfully. MAO inhibitors have several potentially dangerous side effects, so care and close monitoring are necessary in their use. They do give quick relief from a major depression but the patient has to be on a special diet and must remain aware of the possibility of high blood pressure, headaches, and several other side effects. Combined 
use of MAO inhibitors with abused stimulants, depressants, and alcohol can be fatal.

  There are also a number of over-the-counter drugs that should not be taken with MAO inhibitors (PDR, 2000). Monoamine oxidase inhibitors include:

            isocarboxazid (Marplan)

            moclobemide (Aurorix, Manerix, Moclodura)

            phenelzine (Nardil)

            tranylcypromine (Parnate)

            selegiline (Selegiline, Eldepryl), and Emsam

            nialamide

            iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida)

            iproclozide

            toloxatone

     Recently a patch form of the drug called Ensam was invented. Ensam is a transdermal patch for the MAOI antidepressant Selegiline. The FDA approved it in February 2006 for the treatment of depression. Normally, taking Selegiline via tablets requires severe and imperative dietary modification. With Ensam, at least at the lowest dosage, not such dietary modification is requires (Bodkin & Amsterdam, 2002). 

Stimulants

In the past, amphetamine or amphetamine cogeners including Dexadrine Biphetamine, Desoxyn, Ritalin, and Cylert were used to treat depression. They work by increasing the amount of norepinephrine in the central nervous system. They are mood elevators when used in moderation but the problem is that since tolerance develops quickly and the mood lift proved to be too alluring, misuse and addiction developed fairly rapidly. The overuse led to many physical and mental problems such as agitation, aggression, paranoia, and psychosis (Inaba & Cohen, 2000).

Dopamine Reuptake Inhibitors (DARIs)

    Dopamine Transporter Inhibitors are compounds that inhibit the reuptake of extracellular dopamine back into the presynaptic cell by blocking the cell membrane-spanning dopamine transporter. This usually results in an elevated extracellular dopamine level. DARIs bind at the transporter molecule and form a non-covalent complex with it.  As far as the DARI-molecule is large enough (which is normally the case), it suppresses the binding of other substances that are transporter substrates – as endogenous compounds (like dopamine) and drugs (e.g. amphetamine). A very special kind of pseudo-DARIs have been developed by scientists. It is a smaller compound that binds covalently at the transporter, permanently blocks the binding of larger drugs like cocaine,   <>but allows small molecules like dopamine to pass through. A potent dopamine reuptake inhibitor is amineptine which is now banned in most countries including the USA. In general, the abuse potential of DAR inhibitors depends on how they affect the pattern of dopamine release and reuptake. Compounds that inhibit reuptake and also induce release of dopamine (such as methamphetamine or phenmetrazien), or compounds that inhibit reuptake but have no effect on release (such as cocaine) tend to be addictive drugs with potential for abuse. On the other hand, compounds that inhibit reuptake but also inhibit release of dopamine (such as bupropian and vanozerine) have mild stimulant effects and little abuse potential, and can be used to treat stimulant addiction. Dopamine reuptake inhibitors include:  <>

bupropion (Wellbutrin, Zyban)

amineptine (Maneon, Survector)


phenmetrazine (Preludin)


methylphenidate (Ritalin, Rubifen)


vanoxerine (GBR-12909)


CFT (WIN-35428)
 
Mood Stabilizers
 
 
   The APA guideline for the treatment of patients with bipolar disorder does not
recommend monotherapy with an antidepressant for bipolar disorder. The guideline indicates that although combination therapy with lithium and an antidepressant may be appropriate in some circumstances, lithium or lamotrigine should be considered first line options for treatment of acute depression in a patient with bipolar disorder (Preskorn & Flockart, 2006).   

   Manic episodes are characterized by hyperactivity, grandiosity, flight of ideas, and belligerence. Affected patients appear to be euphoric, have racing thoughts, delusions of
  Manic episodes are characterized by hyperactivity, grandiosity, flight of ideas, and belligerence. Affected patients appear to be euphoric, have racing thoughts, delusions of grandeur, and poor if not self-destructive judgment. Periods of depression follow these episodes of mania in the majority of patients. The cycles of this bipolar disorder are typically interspersed among periods of normality that are, in most cases, relatively extended. Mania can usually be managed by chronic treatment with lithium – a mood stabilizer - and can be expected to be effective in 70-80% of the individuals treated. Furthermore, the period of depression that typically follows the manic episode can usually be prevented, or at least attenuated, if lithium treatment is maintained after the manic phase has subsided. Lithium not only controls the period of mania itself but has a prophylactic effect on the subsequent depression. Lithium is no longer the only drug used in the management of mania. Carbamazepine, an anticonvulsant that is used in the treatment of epilepsy, is also useful in the treatment of periods of mania (Carlton, 2002).

   Mood stabilizers are used to prevent or relieve manic or depressive episodes. Mood stabilizing medications that have been effective include lithium and anticonvulsants such as valproic acid, carbamazepine, and lamotrigine. The atypical antipspychotics, such as quetiapine, olanzapine, risperidne, are FDA also approved for acute treatment of mania. Mood stabilizing medications are more effective at treating or preventing manic episodes associated with bipolar disorder – but some medications, such as lamotrigine and fluoxetine have confirmed effectiveness for the treatment of bipolar depression.

   Because mood stabilizers are more effective at treating mania than bipolar depression, periods of depression are sometimes also treated with an antidepressant. There are dangers of inducing mania in the use of antidepressants without mood stabilizers. Treatment guidelines for bipolar depression recommend that antidepressant medication should only be used after a patient has been stabilized on a mood stabilizing medication in order to decrease the risk of a return to mania (Fawcett, J., Golden, B., & Rosenfeld, N. 2000).

     The use of lithium as a treatment of bipolar disorder was first discovered by Dr. John Cade, an Australian psychiatrist who published a paper on the use of lithium in 1949. The two lithium salts used for bipolar therapy are lithium carbonate (mostly) and lithium citrate (sometimes). Approved for the treatment of acute mania in 1970 by the Food and Drug Administration, lithium has been an effective mood-stabilizing medication for many people with bipolar disorder. Lithium is also noted for reducing the risk of suicide (Baldessarini, Tondo, & Hennen, 2003). Although lithium is among the most effective mood stabilizers, persons taking it may experience side effects that are similar to the effects of ingesting too much table salt, such as high blood pressure, water retention, and constipation. Regular blood testing is required when taking lithium to determine the correct lithium levels because the therapeutic dose is close to the toxic dose.

     The mode of action of lithium salt treatment is believed to work as follows: some symptoms of bipolar disorder appear to be caused by the enzyme inositol monophosphatase (IMPase), an enzyme that splits inositol monophosphate into free inositol and phosphate. It is involved in signal transduction and is believed to create an imbalance in the neurotransmitters in bipolar patients. The lithium ion is believed to produce a mood stabilizing effect by inhibiting IMPase by substituting for one of two magnesium ions in IMPase's active site, slowing down this enzyme (Baldessarini, Tondo, & Hennen, 2003).

     Anticonvulsant medications, particularly Valproic acid, have been used as alternatives or adjuncts to lithium in many cases. Valproate (Depakote) is now considered by some doctors to be the first line of therapy for bipolar disorder. For some, it is preferable to lithium because its side effects seem to be less severe, compliance with the medication is better, and fewer breakthrough manic episodes occur. However, valproate is not as effective as lithium in preventing or managing depressive episodes, so patients taking valproate may also need an antidepressant as an adjunct medicinal therapy.

     New research suggests that different combinations of lithium and anticonvulsants may be helpful. Anticonvulsants are also used in combination with antipsychotics. Newer anticonvulsant medications, including lamotrigine and oxcarbazepine, are also effective as mood stabilizers in bipolar disorder. Lamotrigine is particularly promising, as it alleviates bipolar depression and prevents recurrence at higher rates. (Lamont, 2006).

     Topiramate has not done well in clinical trials; it seems to help a few patients very much but most not at all. It appears to be useful in some treatment resistant cases and for anxiety issues when clonazepam cannot be prescribed. Other anticonvulsants effective in some cases and being studied closer include phenytoin, levetiracetam, pregabalin and valnoctamide (Belmaker, Bersudsky, & Mishory (2005).

     In medicine, every medication has its side effects: bipolar disorder medications are no exception. It is important to point out that each medication is associated with a unique side effect profile. Lithium may be associated with gastrointestinal upset (e.g. nausea, diarrhea), memory problems, weight gain and other side effects. Higher doses equal more side effects, but lower doses (within the therapeutic window) have little to no side effects. Anticonvulsant medications commonly cause sedation, weight gain, electrolyte disturbances, or other side effects. If one cannot tolerate one of the anticonvulsants, it's advisable to try another anticonvulsant. Two or more anticonvulsants in combination can often result in a lower effective dose of each and lower side effects.

     Compliance with medications can be a major problem, because some people as they become manic lose the awareness of having an illness, and they therefore discontinue medications. Patients also often quit taking medication when symptoms disappear, mistakenly thinking themselves "cured", and some people enjoy the effects of unmediated hypomania. Other reasons cited by individuals for discontinuing medication are side effects, expense, and the stigma of having a psychiatric disorder. In a relatively small number of cases, patients who do not agree with their psychiatric diagnosis and treatment can legally be required to have treatment without their consent. Throughout North America and the United Kingdom, involuntary treatment or detention laws exist for severe cases of bipolar disorder and other mental illnesses where there is a potential for harm to oneself or others.

Therapy for Depressive disorders

     The role of cognitive processes in the phenomenology, onset, course, and treatment of unipolar depression has been the subject of many scientific investigations. Both Beck’s (1967) theory and the hopelessness theory (Abramson, Metalsky, & Alloy, 1989) are cognitive vulnerability–stress models of depression that view maladaptive cognitive patterns as vulnerabilities that increase the risk both for becoming depressed and for experiencing increased severity and duration of depression when challenged with stressful life events. 

            Although genetic and biological processes are definitely prominent in the etiology, course, and treatment of bipolar disorder (e.g., Goodwin, & Jamison, 1990), biological factors cannot completely explain the differences in the manifestation of the disorder, the timing and frequency of symptoms, or the effectiveness of prophylactic lithium usage. Although psychosocial processes have been somewhat ignored in the study of bipolar mood disorders, a growing body of evidence suggests that stressful life events and environmental factors influence the onset and course of bipolar disorder. Several studies have documented an association between life events and recurrence of manic and depressive episodes in bipolar patients and indicating that negative life events precede manic as well as depressive episodes (Ebmeier, Donaghey, & Steele, 2006).

            The cognitive theories of depression have sought to answer the question of why certain individuals are vulnerable to depression when faced with life stress. According to the attributional vulnerability component of the hopelessness and reformulated helplessness theories of depression (Abrahamson, et al., 1989), individuals who tend to attribute negative events to internal (self), stable (enduring), and global (general) causes are hypothesized to be more likely to experience onset of depression or a worsening of current depression when confronted with stressors than are individuals who do not exhibit this attributional style. In Beck’s (1967) cognitive model of depression, negative self-schemata organized around themes of failure, inadequacy, loss, and worthlessness serve as risk factors for the onset and exacerbation of depression that are activated by the occurrence of stressful life events.

            In Cognitive Behavior Therapy (CBT), the main premise is that depressive symptoms arise from dysfunctional beliefs and thoughts as a result of early learning experiences. These beliefs lie dormant for a number of years, but are activated by a situation or an event that has a specific meaning for the individual. The main focus of CBT is to identify and challenge negative automatic thoughts. Interpersonal therapy is based on the premise that depression occurs in a social and interpersonal context. Interpersonal therapy focuses mainly on present rather than past relationships and on interpersonal rather than intra-psychic processes. Even though the content of interpersonal therapy differs from that of CBT, treatment outcomes for depression are broadly similar (Ebmeier, Donaghey, & Steele, 2006).

The Treatment Process 

            Treating patients with depressive disorders includes education, medication, and psychotherapy. Whichever type of therapy is selected, a rationale for the treatment and an overview of the treatment process, including the goals of therapy (which are best developed and agreed upon by the patient, the therapist and - if applicable - the patient’s family) are considerations of treatment. An important part of the education regarding medication is the drug-drug interactions (DDI) which occur when one drug interferes with the nature, magnitude, or duration of another drug. For this reason, although it is the psychiatrist’s responsibility, it is good practice and extremely important to know the medications that have been prescribed for the patient.

            Although the number of sessions available for patients varies, CBT offers a twenty-week plan using interventions for the newly diagnosed, moving on to interventions for those who are symptomatic, followed by maintenance interventions suitable for patients who have achieved remission. It is helpful to select interventions that match the specific presenting problems of a given patient. For the newly diagnosed patient, education, instructions on lifestyle management and a “Symptom Summary Worksheet” are a good place to start. As the sessions progress, other interventions such as mood graphs, information on and processing of ways to control triggers, management of cognitive and behavioral symptoms, and compliance training are introduced. When symptoms are stabilized, the sessions are geared to relapse prevention, maintenance of adherence to medications and behavioral changes, and the formation, anticipation, and achievement of life goals.

            Concern about drug-drug interaction (DDI) is a necessary part of being involved in the treatment of depressive and other mental disorders. The risk of unintended and dangerous DDIs is increasing as both the number of pharmaceuticals available and the number of patients on multiple medications is increasing. Studies have found that patients on psychiatric medications are on more medications than patients not on psychiatric medications. It is important for treatment providers to appreciate that medications interact not on the basis of their therapeutic use (e.g. Psychiatric vs. cardiac medications) but on the basis of their pharmacodynamics (i.e., Their action on the body) and pharmacokinetics (i.e., the actions of the body on them, including their absorption from the site of administration, their distribution in the body, their metabolism, and their elimination (Preskorn & Flockart, 2006).

            All medications taken by the patient must be considered – including over the counter medications, illicit substances, herbal products, even dietary substances. For example, ibuprofen, an OTC analgesic, can cause serious even life-threatening elevations in lithium levels by affecting its rate of re-absorption (Ragheb, Ban, Buchanan, Frolich, 1980).  Understanding and identifying DDIs with psychiatric medications is perhaps more challenging than in any other area of medicine. The reason is the complexity of the organ they affect. The average human adult is composed of approximately 10–20 billion cells arranged in hierarchal and integrated systems. So far, seventy-five neurotransmitters have been identified in the human brain. Every identified neurotransmitter has several receptor subtypes. Therefore, the human brain may contain thousands of receptors, which are the primary targets of drug action. Consequently, current drugs may interact pharmacodynamically in ways that are neither understood nor predictable at this time (Preskorn, 2006). Their detection is dependent on the careful assessment of the treatment team.

            As psychiatric drugs are more judiciously developed to affect only the brain, their unfavorable effects will not be on peripheral systems but on the brain. Psychiatric DDIs can present as changes in reality testing, emotional control, interpersonal relationships, and memory function. The prescriber of psychiatric medications must be a good behavioral pharmacologist as well as a good diagnostician and clinician - and must also keep in mind that the patient may not be doing well because of the medications he is receiving rather than despite the medications he is receiving Preskorn & Flockart, 2006).

            The 2006 Guide to Psychiatric Drug Interactions (Preskorn & Flockart, 2006) contains tables illustrating the drug-drug interactions and extensive information on known interactions including the differential effects of available antidepressants on CYP enzymes. The antidepressant with the most effects on CYP enzymes are fluoxetine and fluvoxamine. A study by de Leon (2005) found that the co-prescription of risperidone and substantial CYP 2D6 inhibitor such as fluoxetine, produced a greater than three-fold increase in the odds ratio for discontinuation of risperidone due to the development of acute extrapyramidal side effects as compared to individuals on a comparable dose of risperidone but not on a substantial CYP 2D6 inhibitor.

            Preskorn & Flockart (2006) advocate for the use of the simplest drug regimen whenever possible and to always review a patient’s regimen to see if any current medication can be stopped when a new drug is being added. It is critical to have a goal for every drug that is added. If the drug does not meet that goal, then either the dose should be adjusted or the drug should be stopped.

Conclusion

     Treatment of mood disorders is a multifaceted and complicated challenge. It entails the constant exploration, identification, and evaluation of the causes, the components, and the complexity of the human psyche – a relatively unknown entity. Treatment providers face difficult decisions regarding the resolution or easing of the distress experienced by people who have depressive disorders as a part of their living experience. A plethora of information is available – and yet so much has been undiscovered about mental health. Two major concerns as a therapist are to be vigilant regarding DDIs which are so prevalent in psychiatric medications; and to support patients through their challenges with education, guidance, and encouragement. There are many ambiguities and discrepancies in the mysteries surrounding mental disorders. However, one thing is indisputable. Treating people as more than their disease - with respect, unconditional positive regard and with empathy (not sympathy) - is necessary to facilitate growth and healing in any individual.

References   

Abramson, L. Y., Metalsky, G. I. & Alloy, L. B. (1989). Hopelessness depression: A theory-based subtype of depression. Psychological Review, 96, 358-372.

Ainsworth, M., Blehar, M., Waters, E., & Prodromidis, M. (1978). Patterns of attachment: A psychological study of the Strange Situation. Hillsdale, NJ: Eribaum.

American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association.

Baldessarini R., Tondo, L, & Hennen, J. (2003). Lithium treatment and suicide risk in major affective disorders: update and new findings. Journal of Clinical Psychiatry (64)5, 44-52.

Beck, A. T. (1967). Depression: Clinical, experimental, and theoretical aspects. New York, NY: Harper & Row.

Belmaker, R., Bersudsky, Y., & Mishory, A. (2005). Valnoctamide in Mania http://www.clinicaltrials.gov

Bland, R. C. (1997). Epidemiology of Affective Disorders: A Review. Canadian Journal of Psychiatry, 42, 367-377.

Bodkin, J. A. & Amsterdam, J. (2002). Transdermal Selegiline in Major Depression: A Double-Blind, Placebo-Controlled, Parallel-Group Study in Outpatients, American Journal of Psychiatry (159), 1869—1875.

Bowlby, J. (1982). Attachment and Loss: Vol. 1. Attachment. New York: Basic Books. (Original work published 1969).

Carlton, P. (2002). Psychopharmacology, in AccessScience@McGraw-Hill, http://www.accessscience.com.lib-proxy.fullerton.edu, DOI 10.1036/1097-8542.554800, last modified: July 12, 2002.

Cicchetti, D. & Toth, S. (1998). The development of depression in children and adolescents, American Psychologist, 53(2), 221—241.

Crittenden, P. (1988). Relationships at risk. In J. Belsky & T. Nexworski (Eds.) Clinical implications of attachment theory. (pp. 136—174) Hillsdale NJ: Eribaum.

de Leon J, Susce, M., Pan R., Fairchild, M., Koch, W., & Wedlund, P. The CYP2D6 poormetabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. Journal of Clinical Psychiatry, 66(1), 15-27.

Ebmeier, K., Donaghey, C., & Steele, J. (2006). Recent developments and current controversies in depression. Lancet, 367, 253—167.

Fawcett, J., Golden, B., & Rosenfeld, N. 2000). New Hope for People with Bipolar Disorder. Roseville, CA: Prima Health.

Garcia-Sevilla, J., Escriba, P., Ozaitta, A. et al. (1999). Up-regulation of immunolabeled alpha2A-adrenocedptors, GI coupling proteins and regulatory receptor kinase in the prefrontal cortex of depressed suicides. Journal of Neurochemistry (72), 282—291.

Gold, P., Goodwin, E, & Chrousos, G. (1988b). Clinical and biochemical manifestations of depression: Relation to the neurobiology of stress (Part II). New England Journal of Medicine (319), 413-420.

Inaba, D. & Cohen, W. (2000). Uppers, Downers, AllArounders. Ashland, Oregon: Ashland Publications.

Institute of Medicine. (1994). Reducing risks for mental disorders: Frontiers for preventive intervention research. Washington, DC: National Academy Press.

Kandel, D. & Davies, M. (1986). Adult sequelae of adolescent depressive symptoms. Archives of General Psychiatry, (42), 255—262.

Kobak, R., Sudler, N., & Gamble, W. (1991). Attachment and depressive symptoms during adolescence: A developmental pathways analysis. Development and Psychopathology (3), 135—146.

Koob, G. (1996). Drug addiction: the yin and yang of hedonic homeostasis. Neuron (16), 893—896.

Lamot, A. (2006). Lamotrigine for Bipolar Disorder. http://www.psycheducation.org/depression/meds/lamotrigine.htm

Main, M. & Solomon, J. (1990). Procedures for identifying infants as disorganized/disoriented during the Ainsworth Strange Situation. In: Attachment in the preschool years: Theory, research and intervention. Greenberg, M., Cicchetti, D., Cummings, E. Chicago, IL: University of Chicago Press. pp. 121—160.

Malhi, G., Parker, G., & Greenwood, J. (2005). Structural and functional models of depression: from sub-types to substrates, Acta Psychiatr Scand (111), 94—105.

National Mental Health Information Center (2006). Mood Disorders. As found at http://mentalhealth.samhsa.gov on Oct. 20.

PDR. (2002). Physicians Desk Reference (54th ed). Montvale, NJ: Medical Economics Company, Inc.

Pettigrew, J. & Miller, S. (1998). A “Sticky” interhemispheric switch in bipolar disorder? The Royal Society (265), 2141—2148.

Preskorn, S. & Flockart, D. (2006). 2006 Guide to Psychiatric Drug Interactions, Primary Psychiatry (13), 35—64.

Preskorn, S. (2006) Applied Clinical Psychopharmacology. Available at: www.preskorn.com. Accessed November 15, 2006.

Radke-Yarrow, M., Belmont, B., Mottelmann, E., & Bottomly, L. (1990). Young children’s self-conception: Origins in the natural discourse of depressed and normal mothers and their children. In D. Cicchetti & M. Beeghly (Eds.) The self in transition. (pp. 345—361). Chicago: University of Chicago Press.

Ragheb, M., Ban T., Buchanan, D., Frolich, J. (1980). Interaction of indomethacin and  ibuprofen with lithium in manic patients under a steady-state lithium level.  Journal of Clinical Psychiatry, 41(11), 397—398.

Schumacher, Jamra, Becke. (2005). Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biological Pychiatry, 58, 307—314.

Schwartz, M., Bruce A. "Serotonin", in AccessScience@McGraw-Hill, http://www.accessscience.com.lib-proxy.fullerton.edu, DOI 10.1036/1097-8542.616100, last modified: July 15, 2002.

Steingard, R., Renshaw, P., Yurgelvn-Todd, D., Applemans, K., Lyoo, I., Shorrick, K., Bucci, J., Cesenn, M. Ababe, D., Zurakowski, D., Poussaint, T., & Barnes, P. (1996). Structural abnormalities in brain magnetic resonance images of depressed children. Journal of the American Academy of Child and Adolescent Psychiatry (35), 307—31.

Sweetman, S. (2002). Martindale. The complete drug reference, 33, Pharmaceutical Press.           

Weissman, M., Warner, V., Wichramaratne, P., Moreau, D., & Olfson, M. (1997). Offspring of depressed parents 10 years later. Archives of General psychiatry (54), 932—940.