Combination therapy for depression, prevention of suicide, and various medical and psychiatric conditions

• US 7,973,043 B2
• Filed: 07/25/2003
• Issued: 07/05/2011
• Est. Priority Date: 07/30/2002
• Status: Active Grant

• Current Assignee: Peter Migaly
• Original Assignee: Peter Migaly
• Inventors: Migaly, Peter
• Primary Examiner(s): OLSON, ERIC
• Application Number:
  US10/627,358
• Publication Number:
  US 20040204401A1
• Time in Patent Office: 2,902 Days
• Field of Search: 514/259.31
• US Class Current: 514/255.05
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 Antidepressants

Abstract

The present invention relates to a new method of treatment for persons meeting diagnoses for major depressive disorder, or other unipolar (non-bipolar, non-psychotic and non-treatment resistant) depression. The method comprises administering a combination of two categories of drugs, antipsychotics or dopamine system stabilizers, in combination with a newer antidepressant such as a selective serotonin reuptake inhibitor, as initial treatment or as soon as possible. The method targets the prevention of suicide, and provides other benefits including preventing disease progression development of tolerance toward the antidepressants. Another aspect of the invention relates to using the method for alleviating cognitive distortion and related functional impairment or health risks, and/or using the method for smoking cessation or nicotine withdrawal.

Claims

1. A method for treatment of a patient suffering from major depressive disorder, the said method comprising administering to said patient at a time selected from the group consisting of, as an initial treatment, as soon as possible and upon presentation of said patient to a physician or other health care provider an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, combined action SSRI/SNRI, serotonin-2 antagonist/reuptake inhibitors, an antidepressant with alpha-2 antagonism plus serotonin-2 and serotonin-3 antagonism, an antidepressant with serotonin/norepinephrine/dopamine reuptake inhibition, an antidepressant with norepinephrine and dopamine reuptake inhibition, 5-HT-1alpha antagonist, 5-HT-1beta antagonist, 5-HT1A receptor agonists, 5-HT1A receptor agonists and antagonists, 5-HT2 receptor antagonists, viloxazine hydrochloride, dehydroepiandosterone, NMDA receptor antagonists, AMPA receptor potentiators, substance P antagonists/ neurokinin-1 receptor antagonists, nonpeptide Substance P antagonist, neurokinin 2 antagonists, neurokinin 3 antagonists, corticotropin-releasing factor receptor antagonists, antiglucocorticoid medications, glucocorticoid receptor antagonists, cortisol blocking agents, nitric oxide synthesize inhibitors, inhibitors of phosphodiesterase, enkephalinase inhibitors, GABA-A receptor agonists, free radical trapping agents, atypical MAOI'"'"'s, selective MAOI inhibitors, hormones, folinic acid, leucovorin, tramadol, and tryptophan in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of an atypical antipsychotic drug, and a dopamine system stabilizer, and wherein said major depressive disorder categorized as non-treatment resistant and non-psychotic.

3. The method of claims 1 or 2 wherein said antipsychotic drug is an atypical antipsychotic.

4. The method of claim 3 wherein said atypical antipsychotic drug is selected from the group consisting of quetiapine, risperidone, ziprasidone, and pharmaceutically acceptable salts thereof.

5. The method of claim 3 wherein said atypical antipsychotic drug is selected from the group consisting of olanzapine, iloperidone, melperone, amperozide, and pharmaceutically acceptable salts thereof.

6. The method of claims 1 or 2 wherein said antipsychotic drug is a dopamine system stabilizer.

7. The method of claim 6, wherein said dopamine system stabilizer is aripiprazole, or pharmaceutically acceptable salts thereof.

8. The method of claims 1 or 2 wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, and wherein said atypical antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole.

9. The method of claims 1 or 2 wherein said antidepressant is selected from the group consisting of serotonin reuptake inhibitors, a selective norepinephrine reuptake inhibitors, combined action SSRI/SNRI, serotonin-2 antagonist/reuptake inhibitors, an antidepressant with alpha-2 antagonism plus serotonin-2 and serotonin-3 antagonism, an antidepressant with serotonin/norepinephrine/dopamine reuptake inhibition and an antidepressant with norepinephrine and dopamine reuptake inhibition.

10. The method of claims 1 or 2 wherein said antidepressant is selected from the group consisting of 5-HT-I alpha antagonist, 5-HT-I beta antagonist, 5-HTIA receptor agonists, 5-HTIA receptor agonists and antagonists, 5-HT2 receptor antagonists, viloxazine hydrochloride, dehydroepiandosterone, NMDA receptor antagonists, AMPA receptor potentiators, substance P antagonists/neurokinin-1 receptor antagonists, nonpeptide Substance P antagonist, neurokinin 2 antagonists, neurokinin 3 antagonists, corticotropin-releasing factor receptor antagonists, antiglucocorticoid medications, glucocorticoid receptor antagonists, cortisol blocking agents, nitric oxide synthesize inhibitors, inhibitors of phosphodiesterase, enkephalinase inhibitors, GABA-A receptor agonists, free radical trapping agents, atypical MAOI'"'"'s, selective MAOI inhibitors, hormones, folinic acid, leucovorin, tramadol, and tryptophan.

11. The method of claims 1 or 2 wherein said antidepressant is a selective serotonin reuptake inhibitor.

12. The method of claim 9, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof.

13. The method of claim 9, wherein said antidepressant is clomipramine.

14. The method of claim 8, wherein said antidepressant is fluoxetine and said antipsychotic is risperidone.

15. The method of claim 8, wherein said antidepressant is fluoxetine and said antipsychotic is quetiapine.

16. The method of claim 8, wherein said antidepressant is fluoxetine and said antipsychotic is olanzapine.

17. The method of claim 8, wherein said antidepressant is fluoxetine and said antipsychotic is aripiprazole.

18. The method of claim 8, wherein said antidepressant is paroxetine and said antipsychotic is risperidone.

19. The method of claim 8, wherein said antidepressant is paroxetine and said antipsychotic is quetiapine.

20. The method of claim 8, wherein said antidepressant is paroxetine and said antipsychotic is olanzapine.

21. The method of claim 8, wherein said antidepressant is paroxetine and said antipsychotic is aripiprazole.

22. The method of claim 8, wherein said antidepressant is sertraline and said antipsychotic is risperidone.

23. The method of claim 8, wherein said antidepressant is sertraline and said antipsychotic is quetiapine.

24. The method of claim 8, wherein said antidepressant is sertraline and said antipsychotic is olanzapine.

25. The method of claim 8, wherein said antidepressant is sertraline and said antipsychotic is aripiprazole.

26. The method of claim 8, wherein said antidepressant is fluvoxamine and said antipsychotic is risperidone.

27. The method of claim 8, wherein said antidepressant is fluvoxamine and said antipsychotic is quetiapine.

28. The method of claim 8, wherein said antidepressant is fluvoxamine and said antipsychotic is olanzapine.

29. The method of claim 8, wherein said antidepressant is fluvoxamine and said antipsychotic is aripiprazole.

30. The method of claim 8, wherein said antidepressant is fluoxetine and said antipsychotic is ziprasidone.

31. The method of claim 8, wherein said antidepressant is paroxetine and said antipsychotic is ziprasidone.

32. The method of claim 8, wherein said antidepressant is sertraline and said antipsychotic is ziprasidone.

33. The method of claim 8, wherein said antidepressant is fluvoxamine and said antipsychotic is ziprasidone.

34. The method of claim 8, wherein said antipsychotic is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, and the effective amount per day is from 0.5 mg to 4 mg for risperidone, from 25 mg to 400 mg for quetiapine, from 2.5 mg to 10 mg for olanzapine, from 10 mg to 40 mg for ziprasidone, and 2.5 mg to 15 mg for aripiprazole.

35. The method of claims 1 or 2 wherein an effective amount of said antidepressant is its recommended therapeutic dose, or its effective starting dose.

36. The method of claims 1 or 2 wherein the administration is oral.

37. The method of claims 1 or 2, wherein said treatment is given for resisting suicide.

39. The method of claim 1, wherein said treatment is effected for at least one of the group consisting of inhibiting the development of tolerance toward said antidepressant, remedying the development of tolerance toward said antidepressant, avoiding a paradoxical effect of said antidepressant sensitizing said patients to said depression, avoiding worsening of said depression from said antidepressant, and treating worsening of said depression from said antidepressant.

40. The method of claim 11, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, zimelidine, indalpine, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, and wherein said atypical antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole.

41. The method of claim 11, wherein said antidepressant is clomipramine, and wherein said atypical antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole.

43. The method of claim 1 wherein said treatment is effected for treating substantially all of said patients treated by said physician or other health care provider by said method, wherein said treatment is given for resisting suicide.

44. The method of claim 1 including treating a plurality of said patients by said method, wherein said antipsychotic drug is administered at a low dose, and said treatment is given for resisting suicide.

47. The method of claims 1, or 2, wherein said treatment is given for resisting suicide, and wherein said treatment is given for the benefit of the group of said patients being treated by said physician or health care provider.

48. The method of claim 43, 44, 45, or 46 wherein said treatment is given for the benefit of the group of said patients being treated by said physician or health care provider.

49. The method of claims 43 or 45, wherein said antipsychotic drug is an atypical antipsychotic.

50. The method of claims 43 or 45, wherein said atypical antipsychotic drug is selected from the group consisting of quetiapine, risperidone, ziprasidone, and pharmaceutically acceptable salts thereof.

51. The method of claims 43 or 45 wherein said atypical antipsychotic drug is selected from the group consisting of olanzapine, iloperidone, melperone, amperozide, and pharmaceutically acceptable salts thereof.

52. The method of claims 43 or 45 wherein said antipsychotic drug is a dopamine system stabilizer.

54. The method of claims 43 or 45 wherein said antidepressant is selected from the group consisting of serotonin reuptake inhibitors, a selective norepinephrine reuptake inhibitors, combined action SSRI/SNRI, serotonin-2 antagonist/reuptake inhibitors, an antidepressant with alpha-2 antagonism plus serotonin-2 and serotonin-3 antagonism, an antidepressant with serotonin/norepinephrine/dopamine reuptake inhibition and an antidepressant with norepinephrine and dopamine reuptake inhibition.

55. The method of claims 43 or 45 wherein said antidepressant is selected from the group consisting of 5-HT-IaIpha antagonist, 5-HT-Ibeta antagonist, 5-HT1A receptor agonists, 5-HTIA receptor agonists and antagonists, 5-HT2 receptor antagonists, dehydroepiandosterone, NMDA receptor antagonists, AMPA receptor potentiators, substance P antagonists/neurokinin-1 receptor antagonists, nonpeptide Substance P antagonist, neurokinin 2 antagonists, neurokinin 3 antagonists, corticotropin-releasing factor receptor antagonists, antiglucocorticoid medications, glucocorticoid receptor antagonists, cortisol blocking agents, nitric oxide synthesize inhibitors, inhibitors of phosphodiesterase, enkephalinase inhibitors, GABA-A receptor agonists, atypical MAOI'"'"'s, selective MAOI inhibitors, hormones, folinic acid, leucovorin, tramadol, and tryptophan.

56. The method of claims 43 or 45 wherein said antidepressant is a selective serotonin reuptake inhibitor.

59. The method of claims 43 or 45 wherein said antidepressant is fluoxetine and said antipsychotic is risperidone.

60. The method of claims 43 or 45 wherein said antidepressant Is fluoxetine and said antipsychotic is quetiapine.

61. The method of claims 43 or 45 wherein said antidepressant is fluoxetine and said antipsychotic is olanzapine.

62. The method of claims 43 or 45 wherein said antidepressant is fluoxetine and said antipsychotic is aripiprazole.

63. The method of claims 43 or 45 wherein said antidepressant is paroxetine and said antipsychotic is risperidone.

64. The method of claims 43 or 45 whereto said antidepressant is paroxetine and said antipsychotic is quetiapine.

65. The method of claims 43 or 45 wherein said antidepressant is paroxetine and said antipsychotic is olanzapine.

66. The method of claims 43 or 45 wherein said antidepressant is paroxetine and said antipsychotic is aripiprazole.

67. The method of claims 43 or 45 wherein said antidepressant is sertraline and said antipsychotic is risperidone.

68. The method of claims 43 or 45 wherein said antidepressant is sertraline and said antipsychotic is quetiapine.

69. The method of claims 43 or 45 wherein said antidepressant is sertraline and said antipsychotic is olanzapine.

70. The method of claims 43 or 45 Wherein said antidepressant is sertraline and said antipsychotic is aripiprazole.

71. The method of claims 43 or 45 wherein said antidepressant is fluvoxamine and said antipsychotic is risperidone.

72. The method of claims 43 or 45 wherein said antidepressant is fluvoxamine and said antipsychotic is quetiapine.

73. The method of claims 43 or 45 wherein said antidepressant is fluvoxamine and said antipsychotic is olanzapine.

74. The method of claims 43 or 45 wherein said antidepressant is fluvoxamine and said antipsychotic is aripiprazole.

75. The method of claims 43 or 45 wherein said antidepressant is fluoxetine and said antipsychotic is ziprasidone.

76. The method of claims 43 or 45 wherein said antidepressant is paroxetine and said antipsychotic is ziprasidone.

77. The method of claims 43 or 45 whereto said antidepressant is sertraline and said antipsychotic is ziprasidone.

78. The method of claims 43 or 45 wherein said antidepressant is fluvoxamine and said antipsychotic is ziprasidone.

79. The method of claims 43 or 45 wherein said antipsychotic is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, and the effective amount per day is from 0.5 mg to 4 mg for risperidone, from 25 mg to 400 mg for quetiapine, from 2.5 mg to 10 mg for olanzapine, from 10 mg to 40 mg for ziprasidone, and 2.5 mg to 15 mg for aripiprazole.

80. The method of claims 43 or 45 wherein an effective amount of said antidepressant is its recommended therapeutic dose, or its effective starting dose.

81. The method of claims 43 or 45 wherein the administration is oral.

82. The method of claims 43 or 45 wherein said treatment is effected for at least one of the group consisting of delaying relapse;

resisting relapse; and

resisting the recurrence of said depression.

83. The method of claims 43 or 45 wherein said treatment is effected for at least one of the group consisting of protecting against the development of tolerance toward the antidepressant;

and remedying the development of tolerance toward said antidepressant.

84. The method of claims 43 or 45 wherein said treatment is effected for at least one of the group consisting of avoiding a paradoxical effect of said antidepressant sensitizing said patients to said depression;

treating a paradoxical effect of said antidepressant sensitizing said patients to said depression;

for avoiding worsening of said depression from said antidepressant; and

treating worsening of said depression from said antidepressant.

85. The method of claims 43 or 45 wherein said treatment is effected for at least one of the group consisting of avoiding a paradoxical effect of said antidepressant sensitizing said patients to said depression and causing suicide;

avoiding a paradoxical effect of said antidepressant sensitizing said patients to said depression and causing suicidal ideation;

treating a paradoxical effect of said antidepressant sensitizing said patients to said depression and causing suicide;

treating a paradoxical effect of said antidepressant sensitizing said patients to said depression and causing suicidal ideation;

avoiding worsening of said depression from said antidepressant and causing suicide;

avoiding worsening of said depression from said antidepressant and causing suicidal ideation;

treating worsening of said depression from said antidepressant and causing suicide; and

treating worsening of said depression from said antidepressant and causing suicidal ideation.

86. The method of claims 43 or 45 wherein said treatment is given for providing a neuroprotective effect.

87. The method of claims 43 or 45 wherein said treatment is given for treating residual symptoms of said depression.

88. The method of claims 43 or 45 wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof.

89. The method of claims 43 or 45 wherein said antidepressant is clomipramine.

90. The method of claims 43 or 45 wherein said antidepressant is ketamine.

91. The method of claims 43 or 45 wherein said antidepressant is ketamine, and wherein said antipsychotic are selected from the group consisting of perphenazine, trifluoperazine, zotepine, flupenthixol, amisulpride, and sulpiride.

92. The method of claims 43 or 45 wherein said antidepressant is ketamine, and wherein said antipsychotic are selected from the group consisting of risperidone, quetiapine, olanzapine, ziprazidone, and aripriprazole, and the effective amount per day is from 0.5 mg to 4 mg for risperidone, from 25 mg to 400 mg for quetiapine, from 2.5 mg to 10 mg for olanzapine, from 10-40 mg for ziprazidone, and 2.5 mg to 15 mg for aripriprazole.

108. The method of claim 8, wherein said treatment is selected as the first choice of treatment, and said treatment is effected for resisting suicide.

122. The method of claim 1, 2, 114, or 115, wherein a physician or other health care provider is involving said patient in the decision-making of said method by discussing with said patient the risks/benefits, side effects of the medications, wherein discussion of why we cannot continue to refrain using said method is selected from the group comprising at least one of the following steps (a) wherein a said physician or said other health care provider is taking into account the risk/benefit for a group not just for an individual for said combination use of said antidepressants and said antipsychotics, (b) wherein a said physician or said other health care provider in further support of said decision-making of said method is drawing examples for said step (a) selected from the group consisting of (b-1) of how said healthcare providers were treating appendicitis, (b-2) how said healthcare providers are following similar procedures when giving thiamin routinely for everybody in the emergency room before giving intravenous glucose therefore preventing Korsakoff'"'"'s syndrome in alcoholics, and (b-3) how said healthcare providers are routinely testing for drug screen in the emergency room even when the patient says that he or she is absolutely not taking any illicit drugs, therefore said examples (a, b-1, b-2 and b-3) are pointing out that said taking into account the risk/benefit for a group not just for an individual is customary in the medical practice, is a standard procedure and good clinical practice, thus needs to be applied for said method, (c) wherein in this step a said physician or said other health care provider is pointing out that in starting treatment right away with said combination use of said antidepressants and said antipsychotics in all those who are clinically depressed, it is the decrease of suicide rate that is the paramount important factor, (d) and wherein in this step it is pointed out that in the medical profession it would not be fair to continue hiding under the excuses of the added risk of the potential side effects of the antipsychotic medications, specifically with the availability of some of the safer said atypical antipsychotics when in a separate diagnostic category from major depressive disorder, in borderline personality disorder said physicians were not afraid of using the combination of antidepressants with antipsychotic medications and when in comparison, said major depressive disorder has two to two and a half times more risk for committed suicide.

123. The method of claim 122, wherein a said physician or said other health care provider is discussing with said patient other added benefits from the said combination use of said antidepressants and said antipsychotics wherein said added benefits of said treatment is effected for at least one of the group consisting of inhibiting disease progression, modifying the course of said major depressive disorder, inhibiting the development of tolerance toward said antidepressant, remedying the development of tolerance toward said antidepressant, avoiding a paradoxical effect of said antidepressant sensitizing said patients to said major depressive disorder, avoiding worsening of said major depressive disorder from said antidepressant, treating worsening of said major depressive disorder from said antidepressant.

124. The method of claim 1, 2, 114, or 115, wherein the said method is used for the purposes selected from the group consisting of (a) resisting nonadherence to the prescribed medication, (b) resisting said patients discontinuing, said prescribed medication.

125. The method of claim 122, wherein a said physician or said other health care provider is discussing with said patient other reasons and other rationales for using the combination of said antidepressant and said antipsychotic medications in said major depression, wherein said other reasons and other rationales are selected from at least one of the group consisting of the following steps (a) retrospective analysis of suicide committers with major depression showed that many of them have received inadequate treatment (b) it had been shown that among the depressed patients who committed suicide many of them actually had psychotic depression that went unrecognized so they were not receiving antipsychotic medications, (c) cognitive distortions like jumping into conclusions without the analysis of the facts that is prematurely getting into conclusions are characteristic for depression and that it seems that there is an overlap between the cognitive distortions, the mini psychosis of borderline personality disorder, and the full blown psychosis of psychotics, all of them being out of touch with reality but in different degrees and that atypical antipsychotics may be useful for targeting the cognitive distortions that overlap with psychosis (d) and wherein in that step the role of cognitive distortions in hopelessness and suicide is discussed, as a study confirmed the predictive value of hopelessness in suicide, and that hopelessness is the greatest predictor of suicide risk beyond the first year, however suicide occurs in only five per cent of terminally ill patients and their greatest risk factor is untreated depression, therefore it is not hopelessness per se, but its perception, that is the cognitive distortion characteristic of depression, that seems to be the most important factor, and since for strong perceptual disturbances, said physicians had been using said antipsychotics, the adjunctive use of said antipsychotics with said antidepressants in the treatment of said major depressive disorders is supported.

126. The method of claims 122 or 125, wherein said method is used for the purposes selected from the group consisting of (a) resisting nonadherence to the prescribed medication, (b) resisting said patients discontinuing said prescribed medication.

2. A method for treatment of a patient suffering from unipolar depression, the said method comprising administering to said patient at a time selected from the group consisting of, as an initial treatment, as soon as possible and upon presentation of said patient to a physician or other health care provider an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, combined action SSRI/SNRI, serotonin-2 antagonist/reuptake inhibitors, an antidepressant with alpha-2 antagonism plus serotonin-2 and serotonin-3 antagonism, an antidepressant with serotonin/norepinephrine/dopamine reuptake inhibition, an antidepressant with norepinephrine and dopamine reuptake inhibition, 5-HT-1alpha antagonist, 5-HT-1beta antagonist, 5-HT1A receptor agonists, 5-HT1A receptor agonists and antagonists, 5-HT2 receptor antagonists, viloxazine hydrochloride, dehydroepiandosterone, NMDA receptor antagonists, AMPA receptor potentiators, substance P antagonists/ neurokinin-1 receptor antagonists, nonpeptide Substance P antagonist, neurokinin 2 antagonists, neurokinin 3 antagonists, corticotropin-releasing factor receptor antagonists, antiglucocorticoid medications, glucocorticoid receptor antagonists, cortisol blocking agents, nitric oxide synthesize inhibitors, inhibitors of phosphodiesterase, enkephalinase inhibitors, GABA-A receptor agonists, free radical trapping agents, atypical MAOI'"'"'s, selective MAOI inhibitors, hormones, folinic acid, leucovorin, tramadol, and tryptophan in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of an atypical antipsychotic drug, and a dopamine system stabilizer, and wherein said unipolar depression categorized as non-treatment resistant and non-psychotic.

38. The method of claim 2, wherein said treatment is effected for at least one of the group consisting of inhibiting the development of tolerance toward said antidepressant, remedying the development of tolerance toward said antidepressant, avoiding a paradoxical effect of said antidepressant sensitizing said patients to said depression, avoiding worsening of said depression from said antidepressant, and treating worsening of said depression from said antidepressant.

42. The method of claim 2, wherein said treatment is effected for at least one of the group consisting of avoiding a paradoxical effect of said antidepressant sensitizing said patients to said depression, inhibiting worsening of said depression from said antidepressant, and treating worsening of said depression from said antidepressant.

45. The method of claim 2 wherein said treatment is effected for treating substantially all of said patients treated by said physician or other health care provider by said method, and wherein said treatment is given for resisting suicide.

46. The method of claim 2 including treating a plurality of said patients by said method, wherein said antipsychotic drug is administered at a low dose, and said treatment is given for resisting suicide.

53. The method of 43 or 45 wherein said dopamine system stabilizer is aripiprazole, or pharmaceutically acceptable salts thereof.

57. The method of 43 or 45 wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof.

58. The method of 43 or 45 wherein said antidepressant is clomipramine.

93. A method for treatment of a patient suffering from major depressive disorder, said method comprising administering to said patient an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, said major depressive disorder categorized as non-treatment resistant and non-psychotic, and wherein said treatment is effected for at least one of the group consisting of delaying relapse;

resisting relapse; and

resisting the recurrence of said depression.

94. A method for treatment of a patient suffering from unipolar depression, said method comprising administering to said patient an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, said unipolar depression categorized as non-treatment resistant and non-psychotic;

and wherein said treatment is effected for at least one of the group consisting of delaying relapse;

resisting relapse; and

resisting the recurrence of said depression.

95. A method for treatment of a patient suffering from major depressive disorder, said method comprising administering to said patient an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, said major depressive disorder categorized as non-treatment resistant and non-psychotic, and wherein said treatment is effected for at least one of the group consisting of protecting against development of tolerance toward said antidepressant;

and remedying the development of tolerance toward said antidepressant.

96. A method for treatment of a patient suffering from unipolar depression, said method comprising administering to said patient an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, said unipolar depression categorized as non-treatment resistant and non-psychotic;

and wherein said treatment is effected for at least one of the group consisting of protecting against development of tolerance toward said antidepressant; and

remedying the development of tolerance toward said antidepressant.

97. A method for treatment of a patient suffering from major depressive disorder, said method comprising administering to said patient an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, said major depressive disorder categorized as non-treatment resistant and non-psychotic, and wherein said treatment is effected for at least one of the group consisting of avoiding a paradoxical effect of said antidepressant -sensitizing said patients to said depression;

treating a paradoxical effect of said antidepressant sensitizing said patients to .said depression;

for avoiding worsening of said depression from said antidepressant; and

treating worsening of said depression from said antidepressant.

98. A method for treatment of a patient suffering from unipolar depression, said method comprising administering to said patient an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, said unipolar depression categorized as non-treatment resistant and non-psychotic;

and wherein said treatment is effected for at least one of the group consisting of avoiding a paradoxical effect of said antidepressant sensitizing said patients to said depression;

treating a paradoxical effect of said antidepressant sensitizing said patients to said depression;

for avoiding worsening of said depression from said antidepressant; and

treating worsening of said depression from said antidepressant.

99. a method for treatment of a patient suffering from major depressive disorder, said method comprising administering to said patient an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, said major depressive disorder categorized as non-treatment resistant and non-psychotic, and wherein said treatment is effected for at least one of the group consisting of avoiding a paradoxical effect of said antidepressant sensitizing said patients to said depression and causing suicide;

avoiding a paradoxical effect of said antidepressant sensitizing said patients to said depression and causing suicidal ideation;

treating a paradoxical effect of said antidepressant sensitizing said patients to said depression and causing suicide;

treating a paradoxical effect of said antidepressant sensitizing said patients to said depression and causing suicidal ideation;

avoiding worsening of said depression from said antidepressant and causing suicide;

avoiding worsening of said depression from said antidepressant and causing suicidal ideation;

treating worsening of said depression from said antidepressant and causing suicide; and

treating worsening of said depression from said antidepressant and causing suicidal ideation.

100. A method for treatment of a patient suffering from unipolar depression, said method comprising administering to said patient an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, said unipolar depression categorized as non-treatment resistant and non-psychotic;

and wherein said treatment is effected for at least one of the group consisting of avoiding a paradoxical effect of said antidepressant sensitizing said patients to said depression and causing suicide;

avoiding a paradoxical effect of said antidepressant sensitizing said patients to said depression and causing suicidal ideation;

treating a paradoxical effect of said antidepressant sensitizing said patients to said depression and causing suicide;

treating a paradoxical effect of said antidepressant sensitizing said patients to said depression and causing suicidal ideation;

avoiding worsening of said depression from said antidepressant and causing suicide;

avoiding worsening of said depression from said antidepressant and causing suicidal ideation;

treating worsening of said depression from said antidepressant and causing suicide; and

treating worsening of said depression from said antidepressant and causing suicidal ideation.

101. A method for treatment of a patient suffering from major depressive disorder, said method comprising administering to said patient an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, said major depressive disorder categorized as non-treatment resistant and non-psychotic, and wherein said treatment is given for treating residual symptoms of said depression.

102. A method for treatment of a patient suffering from unipolar depression, said method comprising administering to said patient an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, said unipolar depression categorized as non-treatment resistant and non-psychotic;

and wherein said treatment is given for treating residual symptoms of depression.

103. A method for treatment of a patient suffering from unipolar depression, said method comprising administering to said patient an effective amount of an antipsychotic drug wherein said antipsychotic drug is selected from the group consisting of an atypical antipsychotic drug, and a dopamine system stabilizer, wherein said treatment is effected for resisting suicide, and wherein said unipolar depression categorized as non-treatment resistant and non-psychotic.

104. The method of claim 103, wherein said treatment is effected for at least one of the group consisting of avoiding a paradoxical effect of antidepressant sensitizing patients to depression;

treating a paradoxical effect of antidepressant sensitizing patients to depression;

for avoiding worsening of depression from the antidepressant; and

treating worsening of depression from the antidepressant.

105. The method of claim 103, wherein said treatment is effected at a time selected from the group consisting of, as an initial treatment, as soon as possible and upon presentation of said patient to a physician or other health care provider, and wherein said atypical antipsychotic drug or said dopamine system stabilizer is administered at a low dose.

106. The method of claim 103 104, or 105, wherein said atypical antipsychotic or said dopamine system stabilizer is selected from the group consisting of risperidone, olanzapine, ziprasidone and aripiprazole, and the effective amount per day is from 0.5 mg to 4 mg for risperidone, from 2.5 mg to 10 mg for olanzapine, from 10 mg to 40 mg for ziprasidone, and 2.5 mg to 15 mg for aripiprazole.

107. The method of claim 103, 104, or 105, wherein said atypical antipsychotic is quetiapene, and the effective amount per day is from 25 mg to 400 mg.

109. A method for treatment of a patient having cognitive distortions with functional impairment or health hazards, wherein said patient is suffering from major depressive disorder, wherein said major depressive disorder categorized as non-treatment resistant and non-psychotic, wherein said method comprising administering to said patient an effective amount of an antidepressant, wherein said antidepressant is selected from the group consisting of serotonin reuptake inhibitors, a selective norepinephrine reuptake inhibitors, combined action SSRI/SNRI, serotonin-2 antagonist/reuptake inhibitors, an antidepressant with alpha-2 antagonism plus serotonin-2 and serotonin-3 antagonism, an antidepressant with serotonin/norepinephrine/dopamine reuptake inhibition, an antidepressant with norepinephrine and dopamine reuptake inhibition, 5-HT-1alpha antagonist, 5-HT-1beta antagonist, 5-HT1A receptor agonists, 5-HT1A receptor agonists and antagonists, 5-HT2 receptor antagonists, viloxazine hydrochloride, dehydroepiandosterone, NMDA receptor antagonists, AMPA receptor potentiators, substance P antagonists/ neurokinin-1 receptor antagonists, nonpeptide Substance P antagonist, neurokinin 2 antagonists, neurokinin 3 antagonists, corticotropin-releasing factor receptor antagonists, antiglucocorticoid medications, glucocorticoid receptor antagonists, cortisol blocking agents, nitric oxide synthesize inhibitors, inhibitors of phosphodiesterase, enkephalinase inhibitors, GABA-A receptor agonists, free radical trapping agents, atypical MAOI'"'"'s, selective MAOI inhibitors, hormones, folinic acid, leucovorin, tramadol, and tryptophan in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of a typical antipsychotic drug, an atypical antipsychotic drug, and a dopamine system stabilizer.

113. The method of claims 109, 110, or 111 wherein said atypical antipsychotic or said dopamine system stabilizer is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone and aripiprazole, and the effective amount per day is from 0.5 mg to 4 mg for risperidone, from 25 mg to 400 mg for quetiapine, from 2.5 mg to 10 mg for olanzapine, from 10 mg to 40 mg for ziprasidone, and 2.5 mg to 15 mg for aripiprazole.

110. A method for treatment of a patient having cognitive distortions with functional impairment or health hazards, wherein said patient is suffering from major depressive disorder, wherein said major depressive disorder categorized as non-treatment resistant and non-psychotic, wherein the method comprising administering to said patient an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of an atypical antipsychotic drug, and a dopamine system stabilizer and wherein said treatment is effected for resisting suicide.

111. The method of claim 110, wherein said treatment is effected for at least one of the group consisting of avoiding a paradoxical effect of antidepressant sensitizing patients to depression;

treating a paradoxical effect of antidepressant sensitizing patients to depression;

for avoiding worsening of depression from the antidepressant; and

treating worsening of depression from the antidepressant.

112. The method of claim 110, wherein said treatment is effected at a time selected from the group consisting of, as an initial treatment, as soon as possible and upon presentation of said patient to a physician or other health care provider, and wherein said atypical antipsychotic drug or said dopamine system stabilizer is administered at a low dose.

114. A method for treatment of a patient suffering from major depressive disorder, the said method comprising administering to said patient at a time selected from the group consisting of, as an initial treatment, as soon as possible and upon presentation of said patient to a physician or other health care provider an effective amount of an antidepressant, wherein said antidepressant is an antidepressant excluding tricyclic antidepressants, tetracyclic antidepressants and permanent inhibitors of monoamine oxidase and wherein said antidepressant is selected from an antidepressant with final common pathway of antidepressant action associated with the NMDA receptor complex, inducing adaptive changes in the glycine regulatory sites of the NMDA receptor producing a 2-4 fold reduction in the glycine to inhibit 5,7-DCKA binding to the NMDA receptor-associated glycine sites, wherein said antidepressant is used in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of a typical antipsychotic drug, an atypical antipsychotic drug, and a dopamine system stabilizer, and wherein said major depressive disorder categorized as non-treatment resistant and non-psychotic.

116. The method of claims 114 or 115 wherein said atypical antipsychotic drug is selected from the group consisting of quetiapine, risperidone, ziprasidone, olanzapine, iloperidone, melperone, amperozide, and pharmaceutically acceptable salts thereof.

117. The method of claims 114 or 115 wherein said dopamine system stabilizer is aripiprazole, or pharmaceutically acceptable salts thereof.

118. The method of claim 114, or 115, wherein said treatment is effected for at least one of the group consisting of inhibiting the development of tolerance toward said antidepressant, remedying the development of tolerance toward said antidepressant, avoiding a paradoxical effect of said antidepressant sensitizing said patients to said depression, avoiding worsening of said depression from said antidepressant, and treating worsening of said depression from said antidepressant.

119. The method of claim 114, or 115, wherein said treatment is given for resisting suicide.

120. The method of claim 114, or 115, wherein said treatment is effected for treating substantially all of said patients treated by said physician or said other health care provider by said method, and wherein said treatment is given for resisting suicide.

121. The method of claim 114, or 115, wherein said treatment is given for resisting suicide, and wherein said treatment is given for the benefit of the group of said patients being treated by said physician or health care provider.

115. A method for treatment of a patient suffering from unipolar depression, the said method comprising administering to said patient at a time selected from the group consisting of, as an initial treatment, as soon as possible and upon presentation of said patient to a physician or other health care provider an effective amount of an antidepressant, wherein said antidepressant is an antidepressant excluding tricyclic antidepressants, tetracyclic antidepressants and permanent inhibitors of monoamine oxidase and wherein said antidepressant is selected from an antidepressant with final common pathway of antidepressant action associated with the NMDA receptor complex, inducing adaptive changes in the glycine regulatory sites of the NMDA receptor producing a 2-4 fold reduction in the glycine to inhibit 5,7-DCKA binding to the NMDA receptor-associated glycine sites and wherein said antidepressant is used in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of a typical antipsychotic drug, an atypical antipsychotic drug, and a dopamine system stabilizer, and wherein said unipolar depression categorized as non-treatment resistant and non-psychotic.

127. A method for treatment of a patient suffering from major depressive disorder, the said method comprising administering to said patient at a time selected from the group consisting of, as an initial treatment, as soon as possible and upon presentation of said patient to a physician or other health care provider an effective amount of an antidepressant, wherein said antidepressant is a newer antidepressant, and wherein said newer antidepressant is defined as an antidepressant excluding tricyclic antidepressants, tetracyclic antidepressants and permanent inhibitors of monoamine oxidase in combination with an antipsychotic drug, and wherein said major depressive disorder categorized as non-treatment resistant and non-psychotic.

128. The method of claim 127, wherein said antidepressant is selected from the group consisting of fluoxetine, norfluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, bupropion, nefazodone, mirtazapine, venlafaxine, duloxetine, milnacipran, reboxetine, zimelidine, indalpine, gepirone, femoxetine, alaproclate and pharmaceutically acceptable salts thereof, wherein said antipsychotic drug is selected from the group consisting of an atypical antipsychotic and a dopamine system stabilizer, wherein said atypical antipsychotic drug is selected from the group consisting of risperidone, quetiapene, olanzapine, ziprasidone iloperidone, melperone, amperozide, and pharmaceutically acceptable salts thereof, and wherein said dopamine system stabilizer is aripiprazole.

129. A method for treatment of a non-psychotic and non-depressed patient selected from the group consisting of (a) a patient having cognitive distortions with functional impairment or health hazards and (b) of a patient undergoing smoking cessation or nicotine withdrawal, wherein in either case (a) or (b) the method is comprising of administering to said non-psychotic and non-depressed patient an effective amount of a newer antidepressant, wherein said newer antidepressant is defined excluding tricyclic antidepressants, tetracyclic antidepressants and permanent inhibitors of monoamine oxidase in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of an atypical antipsychotic and a dopamine system stabilizer, wherein said antipsychotic drug is administered at a low dose, and wherein said treatment is given for resisting suicide.

130. A method for treatment of a patient suffering from major depressive disorder, the method comprising administering to said patient an effective amount of an antidepressant in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of an atypical antipsychotic drug, and a dopamine system stabilizer, and wherein said major depressive disorder categorized as non-treatment resistant and non-psychotic.

132. The method of claim 130 or 131, wherein treatment is given for resisting suicide.

131. A method for treatment of a patient suffering from unipolar depression, the method comprising administering to said patient an effective amount of an antidepressant in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of an atypical antipsychotic drug, and a dopamine system stabilizer, and wherein said unipolar depression categorized as non-treatment resistant and non-psychotic.

133. The method of claim 131, wherein treatment is effected for at least one of the group consisting of inhibiting the development of tolerance toward the antidepressant, remedying the development of tolerance toward the antidepressant, avoiding a paradoxical effect of antidepressant sensitizing patients to depression, avoiding worsening of depression from the antidepressant, and treating worsening of depression from the antidepressant.